Agents for the prevention or treatment of renal diseases

ABSTRACT

The present invention relates to an agent for the prevention or treatment of a renal disease comprising as an active ingredient a 5-amidino-2- 
                         
hydroxybenzenesulfonamide derivative represented by the general formula:
         wherein R 1  is a hydrogen atom or an optionally substituted alkyl group;   R 2  is a dialkylamino group, an alkyl group, a cycloalkyl group, an optionally substituted aryl group etc.;   T is an oxygen atom, a sulfur atom etc.;   Q is a hydrogen atom or an optionally substituted alkyl group; and Z is a hydrogen atom, a hydroxy group etc.,   or a pharmaceutically acceptable salt thereof which has an inhibitory effect on mesangial cell proliferation and a decreasing effect on protein excretion in urine, and are useful for preventing or treating of various renal diseases such as IgA nephropathy, diabetic nephropathy, nephritic syndrome and the like.

TECHNICAL FIELD

The present invention relates to agents for the prevention or treatmentof renal diseases.

More particularly, the present invention relates to agents for theprevention or treatment of renal diseases comprising as an activeingredient a 5-amidino-2-hydroxybenzenesulfonamide derivative or apharmaceutically acceptable salt thereof.

BACKGROUND ART

Currently, there is concern about the consistent increase in the numberof patients undergoing maintenance hemodialysis, including patients withterminal renal insufficiency, in the field of renal disease. Inaddition, two main underlying diseases for the initiation ofhemodialysis are chronic nephropathy, typically IgA nephropathy, anddiabetic nephropathy which tends to increase remarkably due to changesin life style.

Regarding the pathology of these renal diseases, the increase ofmesangial cells and an extracellular matrix is one of the examples invarious glomerulonephritis including IgA nephropathy. In diabeticnephropathy, microalbuminuria is observed in its early stage, and theincrease in excretion of protein in urine leads to the risk of nephriticsyndrome.

At present, studies of various drugs have been earnestly promoted fordeveloping agents for the prevention or treatment of various renaldiseases (Jpn. J. Pharmacol., Vol. 75, pp. 59-64 (1997); Exp. Nephrol.,Vol. 8, pp. 135-143 (2000); FASEB Journal, Vol. 14, pp. 439-447 (2000);Kidney Int., Vol 59, p 2282 (2001); Kidney Int., Vol. 55, p. 613 (1999);Kidney Int., Vol. 60, p 715 (2001); Diabetes Care, Vol. 13, p. 1114(1990); Kidney Int., Vol. 45, p. 794 (1994)). However, in the abovesituation, the importance and demands have been increasing more andmore, and fast development of novel agents for the prevention ortreatment of various renal diseases has been greatly desired.

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find novel agents forthe prevention or treatment of renal diseases. As a result, it wassurprisingly found that certain 5-amidino-2-hydroxybenzenesulfonamidederivatives possess an excellent inhibitory effect on mesangial cellproliferation and a decreasing effect on urine protein excretion,thereby forming the basis of the present invention.

The present invention has as an object providing novel pharmaceuticalcompositions which are useful for preventing or treating various renaldiseases.

This is, the present invention relates to an agent for the prevention ortreatment of a renal disease comprising as an active ingredient a5-amidino-2-hydroxybenzenesulfonamide derivative represented by thegeneral formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group which mayhave a substituent selected from the following group (A);

-   (A) —COOR^(A), —CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group,    a 6 to 10-membered aryl group, a 3 to 10-membered heterocycloalkyl    group which may have an oxo group, and a 5 to 10-membered aromatic    heterocyclic group which may have an oxo group or a lower alkyl    group;    -   wherein R^(A) represents a hydrogen atom, a 3 to 10-membered        cycloalkyl group or a lower alkyl group which may have a        substituent selected from the following group (i);    -   (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2)        in which R^(A2) is a 3 to 10-membered cycloalkyl group or a        lower alkyl group, —OCOOR^(A3) in which R^(A3) is a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) in        which R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group, —CONR^(A5)R^(A6) in which R^(A5)        and R^(A6) are independently a hydrogen atom or a lower alkyl        group, or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to        10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3        to 10-membered heterocycloalkyl group and a 5 to 10-membered        aromatic heterocyclic group;    -   wherein R^(B) and R^(C) independently represent a hydrogen atom        or a lower alkyl group which may have a substituent selected        from the following group (ii), or —NR^(B)R^(C) forms a cyclic        amino group;    -   (ii) —COOR^(B1) in which R^(B1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group,        —CONR^(B2)R^(C2) in which R^(B2) and R^(C2) are independently a        hydrogen atom or a lower alkyl group, or —NR^(B2)R^(C2) forms a        cyclic amino group, a 3 to 10-membered cycloalkyl group, a 6 to        10-membered aryl group, a 3 to 10-membered heterocycloalkyl        group and a 5 to 10-membered aromatic heterocyclic group;        T represents an oxygen atom, a sulfur atom or a sulfonyl group;        or TR¹ represents —SO₂NR^(B3)R^(C3) in which R^(B3) and R^(C3)        are independently a hydrogen atom or a lower alkyl group;        R² represents a di(lower alkyl)amino group, a lower alkyl group,        a 3 to 10-membered cycloalkyl group, a 6 to 10-membered aryl        group which may have one to three substituents selected from the        following group (B), a 3 to 10-membered heterocycloalkyl group        which may have an oxo group, or a 5 to 10-membered aromatic        heterocyclic group which may have a substituent selected from        the following group (C);-   (B) an oxo group, a lower alkyl group, a halo(lower alkyl) group,    —Y—R^(D), a halogen atom, a nitro group, an amino group, —COOR^(E),    a carbamoyl group, a sulfamoyl group, a lower alkylsulfonyl group, a    mono (lower alkyl) sulfamoyl group which may have —COOR^(F), and a    lower alkylsulfonylamino-substituted (lower alkyl) group;    -   wherein Y represents an oxygen atom or a sulfur atom;    -   R^(D) represents a hydrogen atom, a halo(lower alkyl) group or a        lower alkyl group which may have —COOR^(D1) in which R^(D1) is a        hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower        alkyl group; R^(E) represents a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group;    -   R^(F) represents a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group;-   (C) a lower alkyl group, an amino group and —COOR^(G);    -   wherein R^(G) represents a hydrogen atom, a 3 to 10-membered        cycloalkyl group or a lower alkyl group;        Q represents a hydrogen atom or a lower alkyl group which may        have a substituent selected from the following group (D);-   (D) —OR^(H), —COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl    group which may have one to three substituents selected from the    following group (iii), and a 5 to 10-membered aromatic heterocyclic    group which may have one to three substituents selected from the    following group (iv); wherein R^(H) represents a hydrogen atom or a    lower alkyl group which may have —OR^(H1) in which R^(H1) is a    hydrogen atom or a lower alkyl group;    -   R^(I) independently has the same meaning as R^(A);    -   R^(J) and R^(K) independently represent a hydrogen atom, a 6 to        10-membered aryl group which may have a carbamoyl group, a 5 to        10-membered aromatic heterocyclic group which may have a        substituent selected from the following group (v), or a lower        alkyl group which may have a substituent selected from the        following group (vi), or —NR^(J)R^(K) forms a cyclic amino group        which may have a substituent selected from the following group        (vii);    -   (v) a halogen atom, a lower alkyl group, a carbamoyl group and        —COOR^(J1) in which R^(J1) is a hydrogen atom or a lower alkyl        group;    -   (vi) —OR^(J2) in which R^(J2) is a hydrogen atom or a lower        alkyl group, and a 5 to 10-membered aromatic heterocyclic group;    -   (vii) a hydroxy group, a lower alkyl group, a hydroxy(lower        alkyl) group, a carbamoyl group, a di(lower alkyl)amino group, a        lower acyl group and —COOR^(J3) in which R^(J3) is a hydrogen        atom or a lower alkyl group;    -   (iii) a halogen atom, a nitro group, a lower alkyl group,        —OR^(L) in which R^(L) is a hydrogen atom or a lower alkyl        group, and —COOR^(M) in which R^(M) is a hydrogen atom or a        lower alkyl group;    -   (iv) a halogen atom, an oxo group, a lower alkyl group and a        phenyl group; and        Z represents a hydrogen atom, a hydroxy group or —COOR^(N);        wherein R^(N) represents a halo(lower alkyl) group, a 6 to        10-membered aryl group, or a lower alkyl group which may have a        substituent selected from the following group (viii);    -   (viii) —OR^(N1) in which R^(N1) is a hydrogen atom or a lower        alkyl group, —COOR^(N2) in which R^(N2) is a lower alkyl group        which may have —COOR^(N21) where R^(N21) is a lower alkyl group,        —CONR^(N3)R^(N4) in which R^(N3) and R^(N4) are independently a        hydrogen atom or a lower alkyl group, or —NR^(N3)R^(N4) forms a        cyclic amino group, —OCOR^(N5) in which R^(N5) is a lower alkyl        group which may have —OCOR^(N51) where R^(N51) is a lower alkyl        group, a 3 to 10-membered heterocycloalkyl group and a 6 to        10-membered aryl group;        or a pharmaceutically acceptable salt thereof.

Narrower classes of agents represented by the general formula (I)include:

first, those wherein Q is a hydrogen atom and Z is not a hydrogen atom;or

second, those wherein R¹ is a lower alkyl group having —COOR^(A) whereinR^(A) is a hydrogen atom, a 3 to 10-membered cycloalkyl group or a loweralkyl group which may have a substituent selected from the followinggroup (i);

-   -   (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2)        in which R^(A2) is a 3 to 10-membered cycloalkyl group or a        lower alkyl group, —OCOOR^(A3) in which R^(A3) is a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) in        which R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group, —CONR^(A5)R^(A6) in R^(A5) and        R^(A6) are independently a hydrogen atom or a lower alkyl group,        or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to 10-membered        cycloalkyl group, a 6 to 10-membered aryl group, a 3 to        10-membered heterocycloalkyl group and a 5 to 10-membered        aromatic heterocyclic group;        R² is a phenyl group having a substituent selected from the        following group (B);    -   (B) an oxo group, a lower alkyl group, a halo(lower alkyl)        group, —Y—R^(D), a halogen atom, a nitro group, an amino group,        —COOR^(E), a carbamoyl group, a sulfamoyl group, a lower        alkylsulfonyl group, a mono(lower alkyl)sulfamoyl group which        may have —COOR^(F), and a lower alkylsulfonylamino-substituted        (lower alkyl) group;        -   wherein Y is an oxygen atom or a sulfur atom;        -   R^(D) is a hydrogen atom, a halo(lower alkyl) group or a            lower alkyl group which may have —COOR^(D1) in which R^(D1)            is a hydrogen atom, a 3 to 10-membered cycloalkyl group or a            lower alkyl group;        -   R^(E) is a hydrogen atom, a 3 to 10-membered cycloalkyl            group or a lower alkyl group;        -   R^(F) is a hydrogen atom, a 3 to 10-membered cycloalkyl            group or a lower alkyl group; and            T is an oxygen atom; and Z is a hydroxy group; or            -   third, those wherein R¹ is a methyl group having                —COOR^(A10) wherein R^(A10) is a 3 to 10-membered                cycloalkyl group or a lower alkyl group; and        -   R² is a phenyl group having a substituent selected from the            group consisting of a sulfamoyl group, a lower alkylsulfonyl            group and a mono(lower alkyl)sulfamoyl group; or        -   forth, those wherein R¹ is a lower alkyl group having            —COOR^(A10) wherein R^(A10) is a 3 to 10-membered cycloalkyl            group or a lower alkyl group;        -   R² is a phenyl group having a substituent selected from the            group consisting of a sulfamoyl group, a lower alkylsulfonyl            group and a mono(lower alkyl)sulfamoyl group;        -   Q is a hydrogen atom;        -   T is an oxygen atom; and        -   Z is a hydrogen atom; or        -   a pharmaceutically acceptable salt of these narrower            classes.

The present invention relates to a method for the prevention ortreatment of a renal disease, which comprises administering an effectiveamount of the above 5-amidino-2-hydroxybenzenesulfonamide derivative ora pharmaceutically acceptable salt thereof.

The present invention relates to a use of the above5-amidino-2-hydroxybenzenesulfonamide derivative or a pharmaceuticallyacceptable salt thereof for the manufacture of a pharmaceuticalcomposition for the prevention or treatment of a renal disease.

The present invention also relates to a pharmaceutical composition forthe prevention or treatment of a renal disease comprising as an activeingredient (a) a 5-amidino-2-hydroxybenzenesulfonamide derivative asclaimed in any one of claims 1 to 9 or a pharmaceutically acceptablesalt thereof in combination with at least one drug selected from thegroup consisting of (b) adrenocortical hormone, antiplatelet drugs,adenylate cyclase activators, PGF2α antagonists, cyclooxygenaseinhibitors, adenosine antagonists, GPIIb/IIIa antagonists,anticoagulants and fibrinolytic drugs, immunosuppressant drugs,erythropoietin, fish oil, angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists, glycation inhibitors, proteinkinase C inhibitors, aldose reductase inhibitors, endothelin receptorantagonists, endothelin-converting enzyme inhibitors, neutralendopeptidase inhibitors, thromboxane A₂ synthetase inhibitors,thromboxane A₂ receptor antagonists and PGI₂ analogues.

The present invention also relates to a method for the prevention ortreatment of a renal disease, which comprises administering an effectiveamount of (a) the above 5-amidino-2-hydroxybenzenesulfonamide derivativeor a pharmaceutically acceptable salt thereof, in combination with atleast one drug selected from the group consisting of (b) adrenocorticalhormone, antiplatelet drugs, adenylate cyclase activators, PGF2αantagonists, cyclooxygenase inhibitors, adenosine antagonists,GPIIb/IIIa antagonists, anticoagulants and fibrinolytic drugs,immunosuppressant drugs, erythropoietin, fish oil,angiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists, glycation inhibitors, protein kinase C inhibitors, aldosereductase inhibitors, endothelin receptor antagonists,endothelinconverting enzyme inhibitors, neutral endopeptidaseinhibitors, thromboxane A₂ synthetase inhibitors, thromboxane A₂receptor antagonists and PGI₂ analogues.

The present invention also relates to a use of (a) the above5-amidino-2-hydroxybenzenesulfonamide derivative or a pharmaceuticallyacceptable salt thereof in combination with at least one drug selectedfrom the group consisting of (b) adrenocortical hormone, antiplateletdrugs, adenylate cyclase activators, PGF2α antagonists, cyclooxygenaseinhibitors, adenosine antagonists, GPIIb/IIIa antagonists,anticoagulants and fibrinolytic drugs, immunosuppressant drugs,erythropoietin, fish oil, angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists, glycation inhibitors, proteinkinase C inhibitors, aldose reductase inhibitors, endothelin receptorantagonists, endothelin-converting enzyme inhibitors, neutralendopeptidase inhibitors, thromboxane A₂ synthetase inhibitors,thromboxane A₂ receptor antagonists and PGI₂ analogues, for themanufacture of a pharmaceutical composition for the prevention ortreatment of a renal disease.

More particularly, in a pharmacological test on human activated bloodcoagulation factor X-induced human mesangial cell proliferation, thepresent inventors have confirmed that the compounds of the presentinvention significantly inhibited the proliferation. Thus, the compoundsof the present invention possess a potent inhibitory effect on mesangialcell proliferation, and can prevent the enlargement of an extracellularmatrix due to subsequent collagen accumulation by mesangial cells.Accordingly, the compounds are extremely useful for preventing ortreating various renal diseases in which mesangial cell proliferation isobserved.

Next, in a test for confirming effects on developing nephropathy as theindex of urine protein excretion using db/db mice as spontaneouslydiabetic mice, the present inventors have confirmed that the compoundsof the present invention significantly inhibited albumin excretion intourine. Thus, the compounds of the present invention possess a potentdecreasing effect on urine protein excretion, and therefore, thecompounds are extremely useful for preventing or treating various renaldiseases in which the increase in excretion of protein in urine isobserved.

As mentioned above, the compounds represented by the above generalformula (I) of the present invention have an inhibitory effect onmesangial cell proliferation and a decreasing effect on proteinexcretion in urine, and are useful for preventing or treating of variousrenal diseases in which mesangial cell proliferation or the increase ofprotein excretion in urine is observed. As examples of such renaldiseases, diabetic nephropathy, IgA nephropathy, chronicglomerulonephritis, acute progressive glomerulonephritis, nephriticsyndrome, focal segmental glomerulosclerosis, membranous nephropathy,membranoproliferative glomerulonephritis, crescentic glomerulonephritis,lupus nephritis, purpura nephritis and the like can be illustrated.

Furthermore, in a test for confirming effects on hypercoagulable stateusing db/db mice as spontaneously diabetic mice, the present inventorshave confirmed that the compounds of the present invention significantlyinhibited hypercoagulable state. Thus, the compounds of the presentinvention are extremely useful for preventing or treating renal diseasesaccompanying hypercoagulable state such as diabetic nephropathy due tothis potent inhibitory effect on hypercoagulable state.

The agents for preventing or treating renal diseases of the presentinvention are characterized in comprising as an active ingredient a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I) or a pharmaceutically acceptable salt thereof.In addition, in the present invention, a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I) can be used suitably in combination with atleast one of the following drugs as active ingredients. As examples ofdrugs which can be used in combination with the compound of the abovegeneral formula (I), adrenocortical hormone, antiplatelet drugs,adenylate cyclase activators, PGF2α antagonists, cyclooxygenaseinhibitors, adenosine antagonists, GPIIb/IIIa antagonists,anticoagulants and fibrinolytic drugs, immunosuppressant drugs,erythropoietin, fish oil, angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists, glycation inhibitors, proteinkinase C inhibitors, aldose reductase inhibitors, endothelin receptorantagonists, endothelin-converting enzyme inhibitors, neutralendopeptidase inhibitors, thromboxane A₂ synthetase inhibitors,thromboxane A₂ receptor antagonists, PGI₂ analogues and the like can beillustrated.

In the case of using the compound of the above general formula (I) incombination with the above one or more drugs, the present inventionincludes either dosage forms of simultaneous administration as a singlepreparation or separate preparations by the same or differentadministration routes, and administration at different dosage intervalsas separate preparations by the same or different administration routes.A pharmaceutical composition comprising the compound of the abovegeneral formula (I) in combination with the above drugs includes bothdosage forms as a single preparation and separate preparations incombination as mentioned above.

The compounds of the present invention can provide more advantageouseffects than additive effects in the prevention or treatment of theabove diseases when used suitably in combination with the above one ormore drugs. Also, the administration dose can be decreased in comparisonwith administration of either drug alone, or adverse effects of suchdrugs coadministrated can be avoided or reduced.

Concrete compounds as the above drugs used for combination areexemplified as follows. However, the present invention is not limitedthereto, and concrete compounds include their free compounds, and theirother pharmaceutically acceptable salts.

As adrenocortical hormone, cortisone acetate, prednisolone, prednisolonesodium succinate, prednisolone sodium phosphate, methylprednisolone,methylprednisolone acetate, triamcinolone, dexamethasone, dexamethasonemetasulfobenzoate sodium, dexamethasone sodium phosphate, betamethasone,betamethasone sodium phosphate, prasterone, KSR-592 and the like areillustrated.

As antiplatelet drugs, dilazep dihydrochloride, dipyridamole,cilostazol, alprostadil, iloprost, cloricromene, triflusal, TA-993 andthe like are illustrated.

As adenylate cyclase activators, ticlopidine hydrochloride, colforsindaropate hydrochloride, glucagons, PACAP-38 and the like areillustrated.

As PGF2a antagonists, trimetazidine hydrochloride and the like areillustrated.

As cyclooxygenase inhibitors, aspirin, ketoprofen, tiaprofenic acid,alminoprofen, ibuprofen piconol, flurbiprofen, zaltoprofen, pirprofen,tenoxicam, loxoprofen sodium, oxaprozin, suprofen, fenoprofen,tolfenamic acid, pranoprofen, droxicam, amtolmetin guacil, piroxicamsuccinate, nabmetone, mofezolac, indobufen, lornoxicam, eltenac,ketorolac trometamol, bromfenac sodium hydrate, aceclofenac, diclofenacsodium, cizolirtine citrate, licofelone, S-14080, D-1158, NMI-377,NMI-172, NMI-246, NMI-267, DP-103, MX-1094 and the like are illustrated.

As adenosine antagonists, clopidogrel sulfate, E-3080 and the like areillustrated.

As GPIIb/IIIa antagonists, abciximab, tirofiban hydrochloride,eptifibatide, sibrafiban, roxifiban acetate, gantofiban, cromafiban,elarofiban, YM-337, T-250, DMP-802, UR-3216, YM-68128, HMR-1794,TAK-024, CRL-42796 and the like are illustrated.

As anticoagulants and fibrinolytic drugs, heparin, warfarin, urokinaseand the like are illustrated.

As immunosuppressant drugs, azathioprine, cyclophosphamide, mizoribine,ciclosporin, tacrolimus hydrate, chlorambucil, lobenzarit disodium,auranofin, alprostadil, gusperimus hydrochloride, biosynsorb, muromonab,alefacept, pentostatin, daclizumab, sirolimus, mycophenolate mofetil,leflonomide, basiliximab, dornase α, bindarid, cladribine, pimecrolimus,ilodecakin, cedelizumab, efalizumab, everolimus, anisperimus,gavilimomab, faralimomab, clofarabine, siplizumab, saireito, LDP-03,CD4, SR-43551, SK&F-106615, IDEC-114, IDEC-131, FTY-720, TSK-204,LF-080299, A-86281, A-802715, GVH-313, HMR-1279, ZD-7349, IPL-423323,CBP-1011, MT-1345, CNI-1493, CBP-2011, J-695, LJP-920, L-732531,ABX-RB2, AP-1903, IDPS, BMS-205820, BMS-224818, CTLA4-1g, ER-49890,ER-38925, ISAtx-247, RDP-58, PNU-156804, LJP-1082, TMC-95A, TV-4710,PTR-262-MG, AGI-1096 and the like are illustrated.

As angiotensin-converting enzyme inhibitors, lisinopril, ramipril,fosinopril, enalapril maleate, captopril, alacepril, delaprilhydrochloride, benzapril hydrochloride, quinaprilat, imidaprilhydrochloride, zofenopril calcium, fosinopril sodium, cilazapril,temocapril hydrochloride, spirapril hydrochloride, quinaprilhydrochloride, perindopril erbumine, moexipril hydrochloride,trandolapril, MDL-100240, SA-7060, E-4030, GW-660511 and the like areillustrated.

As angiotensin II receptor antagonists, losartan potassium, valsartan,irbesartan, candesartan cilexetil, eprosartan mesilate, telmisartan,olmesartan, Dup753, PD123177, EXP-3174, EXP-3312, KT-3-671, RU-64276,GA-0113, CS-088 and the like are illustrated.

As glycation inhibitors, pimagedine hydrochloride, ALT-711, EXO-226,KGR-1380, ALT-711 and the like are illustrated.

As protein kinase C inhibitors, midostaurin, perifosine, LY333531,KW-2401, ISIS-3521, ISIS-5132 and the like are illustrated.

As aldose reductase inhibitors, epalrestat, risarestat, fidarestat,tolrestat, zopolrestat, minalrestat, ascorbyl gamolenate, lindolrestat,AD-5467, AS-3201, NZ-314, SG-210, IDD-598, JTT-811 and the like areillustrated.

As endothelin receptor antagonists, bosentan, sitaxsentan sodium,darusentan, atrasentan, tezosentan sodium, ambrisentan, BMS-207940,BMS-193884, S-0139, BQ-610, TA-0201, SB-215355, SB-234551, SB-247083,J-104132, RO-61-1790, PD-180988, LU-302872, TBC-3214, TBC-3711,RPR-118031A, ABT-546, ATZ-1993, YM-598 and the like are illustrated.

As endothelin-converting enzyme inhibitors, SLV-306, CGS-35066, SM-19712and the like are illustrated.

As neutral endopeptidase inhibitors, omapatrilat, fasidotril, ecadotril,sampatrilat, MDL-100240, SA-7060, SLV-306, E-4030, GW-660511X and thelike are illustrated.

As thromboxane A₂ synthetase inhibitors, sodium ozagrel, ozagrelhydrochloride, isbogrel, terbogrel, imitrodast sodium, imidazolsalicylate, NM-702, S-32080, NIK-639 and the like are illustrated.

As thromboxane A₂ receptor antagonists, egualen sodium, seratrodast,ramatroban, epoprostenol sodium, domitroban calcium hydrate, ibudilast,phthalazinol, KT-2-962, Z-335, S-18204, YM-158, S-32080, S-36496,S-35120 and the like are illustrated.

As PGI₂ analogues, beraprost sodium, iloprost, clinprost, pimilprost,TY-11223 and the like are illustrated.

In the compounds represented by the above general formula (I) of thepresent invention as an active ingredient, the substituent R¹ ispreferably a lower alkyl group having —COOR^(A) wherein R^(A) has thesame meaning as defined above, and more preferably a methyl group having—COOR^(A10) wherein R^(A10) is a 3 to 10-membered cycloalkyl group or alower alkyl group. The substituent R² is preferably a phenyl grouphaving a substituent selected from the above group (B), and thesubstituent is preferably at the p-position. Furthermore, thesubstituent R² is more preferably a phenyl group having a substituentselected from the group consisting of a sulfamoyl group, a loweralkylsulfonyl group and a mono (lower alkyl) sulfamoyl group, and mostpreferably a phenyl group having a lower alkylsulfonyl group. Thesubstituent Q is preferably a hydrogen atom. The substituent T ispreferably an oxygen atom. The substituent Z is preferably a hydroxygroup or —COOR^(N) wherein R^(N) has the same meaning as defined above,and more preferably a hydroxy group. Compounds having such a substituentZ and pharmaceutically acceptable salts thereof are excellent compoundswhich can exert a favorable activated blood coagulation factor Xinhibitory activity when they are orally administered. As the compoundsrepresented by the above general formula (I) of the present invention,ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate,isopropyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate,n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateand cyclohexyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateare preferable, and isopropyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate,n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateand cyclohexyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateare more preferable.

In the present invention, the term “lower alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a pentyl group, anisopentyl group, a neopentyl group, a 1-methylbutyl group, a2-methylbutyl group, a hexyl group or the like. The term “loweralkylsulfonyl group” means a sulfonyl group having the above lower alkylgroup, such as a methanesulfonyl group, an ethanesulfonyl group, apropane-sulfonyl group, an isopropanesulfonyl group, a butanesulfonylgroup, an isobutanesulfonyl group, a sec-butanesulfonyl group, apentanesulfonyl group, an isopentanesulfonyl group, a neopentanesulfonylgroup, a hexanesulfonyl group or the like. The term “mono (lower alkyl)sulfamoyl group” means a monoalkylsulfamoyl group wherein the alkylmoiety is the same as the above lower alkyl group. The term “di (loweralkyl)amino group” means an amino group di-substituted by the same ordifferent lower alkyl groups as defined above. The term “loweralkylsulfonylamino-substituted (lower alkyl) group” means the abovealkyl group having an amino group N-substituted by the above loweralkylsulfonyl group. The term “hydroxy(lower alkyl) group” means astraight-chained or branched alkyl group having 2 to 6 carbon atoms andsubstituted by a hydroxy group. The term “lower acyl group” means astraight-chained or branched alkoxycarbonyl group having 2 to 6 carbonatoms such as an acetyl group, a propionyl group, a butyryl group, anisobutyryl group, a valeryl group, a hexanoyl group or the like. Theterm “lower alkylene group” means a straight-chained or branchedalkylene group having 1 to 6 carbon atoms such as a methylene group, anethylene group, a trimethylene group, a propylene group or the like.

The term “3 to 10-membered cycloalkyl group” means a 3 to 7-memberedmonocyclic aliphatic alkyl group such as a cyclopropyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group or acycloheptyl group, or a cyclopentyl group or a cyclohexyl group whichare fused with a benzene ring. The term “6 to 10-membered aryl group”means a phenyl group, a naphthyl group, or a phenyl group which is fusedwith a cyclopentane ring or a cyclohexane ring.

The term “3 to 10-membered heterocycloalkyl group” means a 3 to7-membered monocyclic heteroalkyl group containing one to two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom inthe ring, or a bicyclic heteroalkyl group which is benzene fused with a5 or 6-membered monocyclic heteroalkyl group as defined above, and asexamples of such groups, for example, a monovalent group derived frommorpholine, thiomorpholine, pyrrolidine, imidazoline, oxazoline,piperidine, piperazine, tetrahydrofuran, aziridine, azetidine, indoline,isoindoline, chroman, isochroman or the like can be illustrated. Asexamples of heterocycloalkyl groups having an oxo group, for example, amonovalent group derived from a 2-oxazolidone or the like can beillustrated.

The term “5 to 10-membered aromatic heterocyclic group” means a 5 to6-membered monocyclic aromatic group containing one to four hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom in thering, or a bicyclic heteroalkyl group which is benzene or pyridine fusedwith a 5 or 6-membered monocyclic aromatic group as defined above, andas examples of such groups, for example, a monovalent group derived frompyridine, pyrimidine, pyrazine, pyridazine, pyrrole, thiophene, oxazole,thiazole, imidazole, pyrazole, oxadiazole, thiodiazole, tetrazole,indole, indolizine, benzofuran, benzothiophene, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or thelike can be illustrated. As examples of aromatic heterocyclic grouphaving an oxo group, for example, a monovalent group derived from a1,3,4-oxadiazol-2-one or the like can be illustrated.

The term “cyclic amino group” means a 5 to 6-membered monocyclic aminogroup which may contain one hetero atom selected from a nitrogen atom,an oxygen atom and a sulfur atom other than the nitrogen atom at thebinding site in the ring, such as a 1-pyrrolidinyl group, a piperidinogroup, a morpholino group, a thiomorpholino group, a 1-piperazinyl groupor the like.

The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom or an iodine atom. The term “halo(lower alkyl) group” meansthe above alkyl group substituted by one to three halogen atom asdefined above, such as a trifluoromethyl group, a 2,2,2-trifluoroethylgroup or the like.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared by allowing a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) or a salt thereof to react with an alcohol in thepresence of hydrogen chloride (hereinafter referred to as Process 1),allowing the resulting compound to react with ammonia or a salt thereof,or hydroxylamine or a salt thereof (hereinafter referred to as Process2), carrying out, as occasion demands, suitably one to four processesselected from the group consisting of (1) hydrolysis of the resultingester group (hereinafter referred to as Process 3), (2) esterinterchange or esterification of the resulting compound using an alcoholcompound represented by the general formula:R^(A)—OH  [III]

wherein R^(A) has the same meaning as defined above, or esterificationof the resulting compound using a compound represented by the generalformula:R^(A)—X¹  [IV]

wherein X¹ represents a leaving group such as a halogen atom, atoluenesulfonyloxy group, a methanesulfonyloxy group or the like; andR^(A) has the same meaning as defined above (hereinafter referred to asProcess 4), (3) introduction of a protective group into a phenolichydroxy group (hereinafter referred to as Process 5) and (4) N-acylationof the resulting compound using a compound represented by the generalformula:R^(N)OCO—X²  [V]

wherein X² represents a leaving group such as a halogen atom, a4-nitrophenoxy group or the like; and R^(N) has the same meaning asdefined above, and subjecting, as occasion demands, to removal of theprotective group of the phenolic hydroxy group or O-deacylation in theusual way.

In the aforementioned production process, the reaction from a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) into a 5-amidino-2-hydroxybenzenesulfonamidederivative represented by the above general formula (I) is as follows indetail.

Process 1

A corresponding imidate compound can be prepared by allowing a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) to react with an alcohol such as methanol orethanol in the presence of a hydrogen halide such as hydrogen chlorideor hydrogen bromide usually at −20° C. to room temperature. As a solventused, methanol, ethanol, a mixed solvent of such alcohol withtetrahydrofuran, dichloromethane or N,N-dimethylformamide, and the likecan be illustrated. The reaction time is usually from 1 hour to 3 days,varying based on the type and volume of starting material and solventused.

Process 2

A corresponding amidino compound can be prepared by allowing an imidatecompound to react with ammonia or an ammonium salt such as ammoniumcarbonate, ammonium chloride or ammonium acetate, or hydroxylamine or asalt thereof in the presence or absence of a base such as triethylamineusually at 0° C. to room temperature. As a solvent used, methanol,ethanol, tetrahydrofuran, dichloromethane and the like can beillustrated. The reaction time is usually from 1 hour to 3 days, varyingbased on the type and volume of starting material and solvent used.

Process 3

In the case of compounds having an ester group in the amidinoderivatives obtained by Process 2, a corresponding carboxylic acidcompound can be prepared by subjecting such compound to hydrolysis usingan acid such as hydrochloric acid or sulfuric acid, usually at roomtemperature to reflux temperature, or a base such as sodium hydroxide,usually at 0° C. to reflux temperature. As a solvent used, water,acetonitrile, tetrahydrofuran, alcohols, a mixed solvent thereof and thelike can be illustrated. The reaction time is usually from 1 hour to 2days, varying based on the type and volume of starting material andsolvent used.

Process 4

A corresponding ester compound can be prepared by 1) subjecting anamidino derivative having an ester group or a carboxy group obtained byProcess 2 or 3 to ester interchange or esterification using an alcoholcompound represented by the above general formula (III) in the presenceof an acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonicacid usually at 0° C. to reflux temperature, by 2) subjecting a compoundhaving a carboxy group of the amidino derivatives obtained by Process 2or 3 to esterification using an alcohol compound represented by theabove general formula (III) in the presence of a condensing agent suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride usuallyat 0° C. to reflux temperature, or by 3) subjecting a compound having acarboxy group of the amidino derivatives obtained by Process 2 or 3 toesterification using a compound represented by the above general formula(IV) in the presence of a base such as potassium carbonate ortriethylamine, or silver carbonate usually at 0° C. to refluxtemperature. As a solvent used, an aprotic solvent such astetrahydrofuran and the like can be illustrated. The reaction time isusually from 1 hour to 2 days, varying based on the type and volume ofstarting material and solvent used.

Process 5

A corresponding O-protected compound can be prepared by suitablyprotecting a phenolic hydroxy group of a compound having an amidinogroup obtained by Processes 2-4 according to a method described inPROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE, PETER G WUTSby JOHN WILEY & SONS, INC.

Process 6

A corresponding carbamate compound can be prepared by allowing acompound having an amidino group obtained by Processes 2-5 to react witha compound represented by the above general formula (V) in the presenceor absence of a base such as triethylamine or diisopropylethylamineusually at 0° C. to room temperature. As a solvent used,N,N-dimethylformamide and the like can be illustrated. The reaction timeis usually from 1 hour to 2 days, varying based on the type and volumeof starting material and solvent used.

The removal of the protective group of the hydroxy group can be commonlycarried out according to a method described in PROTECTIVE GROUPS INORGANIC SYNTHESIS, THEODORA W. GREENE, PETER G. WUTS by JOHN WILEY &SONS, INC.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound represented by the general formula:

wherein Q, R¹, R² and T have the same meanings as defined above, can bealso prepared by allowing a 5-cyano-2-hydroxybenzenesulfonamidederivative represented by the above general formula (II) or a saltthereof to react with hydroxylamine or a salt thereof in the presence orabsence of a base (hereinafter referred to as Process 9), andsubjecting, as occasion demands, the resulting compound to esterinterchange or esterification using an alcohol compound represented bythe above general formula (III), or to esterification using a compoundrepresented by the above general formula (IV) (hereinafter referred toas Process 10). In the case that 5-cyano-2-hydroxybenzenesulfonamidederivatives represented by the above general formula (II) as startingmaterials have a carboxy group, it is preferable that Process 9 iscarried out after converting it into an inorganic salt of acorresponding carboxylic acid (e.g. a sodium salt, a potassium salt)(hereinafter referred to as Process 8). In the case that5-cyano-2-hydroxybenzenesulfonamide derivatives represented by the abovegeneral formula (II) as starting materials have an ester group, it ispreferable that Process 9 is carried out after hydrolysis of the estergroup (hereinafter referred to as Process 7) and Process 8.

In the aforementioned production process, the reaction from a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) into a 5-amidino-2-hydroxybenzenesulfonamidederivative represented by the above general formula (Ia) is as followsin detail.

Process 7

A corresponding carboxylic acid compound can be prepared by subjecting acorresponding 5-cyano-2-hydroxybenzenesulfonamide derivative having anester group to hydrolysis using an acid such as hydrochloric acid orsulfuric acid usually at room temperature to reflux temperature, orusing a base such as sodium hydroxide usually at 0° C. to refluxtemperature. As a solvent used, water, acetonitrile, tetrahydrofuran,alcohols, a mixed solvent thereof and the like can be illustrated. Thereaction time is usually from 1 hour to 2 days, varying based on thetype and volume of starting material and solvent used.

Process 8

A corresponding 5-cyano-2-hydroxybenzenesulfonamide derivative having acarboxy group can be converted by treating with a base such as sodiumhydroxide or potassium hydroxide in the presence of various solvents orwithout any solvent usually at −20° C. to room temperature into acorresponding inorganic salt of the carboxylic acid compound. As asolvent used, water, ethanol, tetrahydrofuran, a mixed solvent thereofand the like can be illustrated. The reaction time is usually from 1hour to 2 days, varying based on the type and volume of startingmaterial and solvent used.

Process 9

A corresponding amidoxime compound can be prepared by allowing a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II), which is obtained by treating according toProcesses 7 and 8 as occasion demands, to react with hydroxylamine or asalt thereof in the presence or absence of a base such as triethylamineusually at 50° C. to reflux temperature. As a solvent used, water,methanol, ethanol, tetrahydrofuran, toluene, a mixed solvent thereof andthe like can be illustrated. The reaction time is usually from 1 hour to3 days, varying based on the type and volume of starting material andsolvent used.

Process 10

A corresponding ester compound can be prepared by 1) subjecting anamidoxime compound having an ester group or a carboxy group obtained byProcess 9 to ester interchange or esterification using an alcoholcompound represented by the above general formula (III) in the presenceof an acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonicacid usually at 0° C. to reflux temperature, by 2) subjecting anamidoxime derivative having a carboxy group obtained by Process 9 toesterification using an alcohol compound represented by the abovegeneral formula (III) in the presence of a condensing agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride usually at0° C. to reflux temperature, or by 3) subjecting an amidino derivativehaving a carboxy group obtained by Process 9 to esterification using acompound represented by the above general formula (IV) in the presenceof a base such as potassium carbonate or triethylamine, or silvercarbonate, usually at 0° C. to reflux temperature. As a solvent used, anaprotic solvent such as tetrahydrofuran and the like can be illustrated.The reaction time is usually from 1 hour to 2 days, varying based on thetype and volume of starting material and solvent used.

Of the compounds represented by the above general formula (I),

a compound represented by the general formula:

wherein R³ represents —COOR^(A7) in which R^(A7) is a lower alkyl grouphaving —CONR^(A5)R^(A6) where R^(A5) and R^(A6), or —NR^(A5)R^(A6) havethe same meanings as defined above, or a lower alkyl group having—CONR^(B)R^(C) where R^(B) and R^(C), or —NR^(B)R^(C) have the samemeanings as defined above; and R², Q, T and Z have the same meanings asdefined above, can be prepared by allowing a compound represented by thegeneral formula:

wherein R⁴ represents —COOR^(A8) in which R^(A8) is a hydrogen atom or alower alkyl group having —COOH; and R², Q, T and Z have the samemeanings as defined above, or a salt thereof to react with an aminecompound represented by the general formula:HNR^(A5)R^(A6)  [VI]

wherein R^(A5) and R^(A6) or —NR^(A5)R^(A6) have the same meanings asdefined above, or a salt thereof, or to react with an amine compoundrepresented by the general formula:HNR^(B)R^(C)  [VII]

wherein R^(A5) and R^(A6), or —NR^(A5)R^(A6) have the same meanings asdefined above, or a salt thereof (hereinafter referred to as Process11).

In the aforementioned production process, the reaction from a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (Ic) into a 5-amidino-2-hydroxybenzenesulfonamidederivative represented by the above general formula (Ib) is as followsin detail.

Process 11

A 5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (Ib) can be prepared by allowing a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (Ic) or a salt thereof to react with an aminecompound represented by the above general formula (VI) or a saltthereof, or to react with an amine compound represented by the abovegeneral formula (VII) or a salt thereof in the presence of a condensingagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, diphenylphosphoryl azide or the like and in the presenceor absence of an agent for making an activated ester such as1-hydroxybenzotriazole monohydrate and a base such as triethylamineusually at 0° C. to room temperature. As a solvent used,dichloromethane, N,N-dimethylformamide and the like can be illustrated.The reaction time is usually from 1 hour to 2 days, varying based on thetype and volume of starting material and solvent used.

For example, the 5-cyano-2-hydroxybenzenesulfonamide derivativesrepresented by the above general formula (II) used as starting materialsin the aforementioned production processes can be prepared by thefollowing method:

wherein R⁵ represents a lower alkyl group which may have a substituentselected from the following group (A);

(A) —COOR^(A), —CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group, a 6to 10-membered aryl group, a 3 to 10-membered heterocycloalkyl groupwhich may have an oxo group, and a 5 to 10-membered aromaticheterocyclic group which may have an oxo group or a lower alkyl group;

wherein R^(A), R^(B) and R^(C), or —NR^(B)R^(C) have the same meaningsas defined above;

R⁶ represents a halogen atom, a hydroxy group, a di(lower alkyl)aminogroup, a lower alkyl group, a 3 to 10-membered cycloalkyl group, or a 3to 10-membered heterocycloalkyl group which may have an oxo group;

R⁷ represents a 5 to 10-membered aromatic heterocyclic group which mayhave a substituent selected from the following group (C), or a 6 to10-membered aryl group which may have one to three substituents selectedfrom the following group (E);

(C) a lower alkyl group, an amino group and —COOR^(G) in which R^(G) hasthe same meaning as defined above;

(E) an oxo group, a lower alkyl group, a halo(lower alkyl) group,—Y—R^(D), a halogen atom, a nitro group, an amino group, —COOR^(E), acarbamoyl group, a sulfamoyl group, a mono (lower alkyl) sulfamoyl groupwhich may have —COOR^(F), and a lower alkylsulfonylamino-substituted(lower alkyl) group;

wherein R^(D), R^(E), R^(F) and Y have the same meanings as definedabove

R⁸ represents a hydrogen atom or a lower alkyl group, or both of R⁸ bindto form a lower alkylene group;

Q¹ represents a lower alkyl group which may have a substituent selectedfrom the following group (D);

(D) —OR^(H), —COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl groupwhich may have one to three substituents selected from the followinggroup (iii), and a 5 to 10-membered aromatic heterocyclic group whichmay have one to three substituents selected from the following group(iv);

wherein R^(H), R^(I), R^(J) and R^(K), or —NR^(J)R^(K) have the samemeanings as defined above;

(iii) a halogen atom, a nitro group, a lower alkyl group, —OR^(L) inwhich R^(L) has the same meaning as defined above, and —COOR^(M) inwhich R^(M) has the same meaning as defined above;

(iv) a halogen atom, an oxo group, a lower alkyl group and a phenylgroup; and

T¹ represents an oxygen atom or a sulfur atom;

X³ represents a chlorine atom, a bromine atom or an iodine atom;

X⁴ represents a chlorine atom, a bromine atom or an iodine atom; and

Q, R¹, R² and T have the same meanings as defined above.

Process A

A benzenesulfonamide derivative represented by the above general formula(X) can be prepared by condensing a benzene-sulfonyl halide derivativerepresented by the above general formula (VIII) with a phenethylaminederivative represented by the above general formula (IX) or a saltthereof in the presence or absence of a base such as triethylamine orpotassium carbonate in a polar solvent such as tetrahydrofuran,N,N-dimethylformamide, or a mixed solvent of such solvent with waterusually at 0° C. to room temperature.

Process B

A benzenesulfonamide derivative represented by the above general formula(XII) can be prepared by condensing a benzene-sulfonamide derivativewherein R⁶ is a hydroxy group represented by the above general formula(X) with a trifluoromethanesulfonic anhydride represented by the abovegeneral formula (XI) in the presence of a base such asN,N-dimethylaminopyridine in a solvent such as dichloromethane,tetrahydrofuran usually at 0° C. to reflux temperature.

Process C

A benzenesulfonamide derivative represented by the above general formula(XIV) can be prepared by condensing a benzene-sulfonamide derivativerepresented by the above general formula (XII) or a benzenesulfonamidederivative wherein R⁶ is a halogen atom represented by the above generalformula (X) with a boron compound represented by the above generalformula (XIII) in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0), palladium(II) acetate or[1,1′-bis(diphenylphosphino)ferrocene]chloronickel(II) and a base suchas sodium carbonate, sodium hydrogen carbonate, potassium phosphate ortriethylamine and in the presence or absence of a phase-transfercatalyst such as tetrabutylammonium bromide in a solvent such astoluene, tatrahydrofuran, N,N-dimethyl-formamide or water, or a mixedsolvent thereof usually at room temperature to reflux temperature.

Process D

A compound wherein R⁷ is a (lower alkyl)thioaryl group and/or T¹ is asulfur atom of a compound represented by the above general formula (XIV)can be converted into a corresponding sulfonyl compound by treating itwith an oxidizing agent such as Oxone (trademark) or m-chloroperbenzoicacid in a solvent such as acetone or dichloromethane, or a mixed solventof such solvent with water usually at 0° C. to reflux temperature.

Process E

A compound of the above general formula (X) or (XIV), or a compoundwherein T¹ is an oxygen atom and R⁵ is a benzyl group of a compoundrepresented by the above general formula (XIV) wherein R⁷ is a (loweralkyl) thioaryl group oxidizing the sulfur atom can be converted into acorresponding phenol compound represented by the above general formula(XV) by subjecting it to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon or palladium hydroxide in a hydrogenatmosphere in a polar solvent such as ethanol usually at roomtemperature to reflux temperature and at atmospheric pressure or appliedpressure to remove the benzyl group. This process can be similarlycarried out using a compound wherein T¹ or T is an oxygen atom and R¹ isa benzyl group after the following Process F or G.

Process F

A corresponding N-alkylated compound can be prepared by subjecting acompound represented by the above general formula (XV) to N-alkylationusing an alkylating agent represented by the above general formula (XVI)in the presence of a base such as triethylamine or potassium carbonatein a solvent such as N,N-dimethylformamide usually at −20° C. to refluxtemperature.

Process G

A benzenesulfonamide derivative represented by the above general formula(II) can be prepared by subjecting a compound of the above generalformula (XV) or a compound N-alkylated by Process F to demethylationunder heating in the presence of lithium chloride in a solvent such asN,N-dimethylformamide or N,N-dimethylacetamide usually at 100° C. toreflux temperature.

For example, of a compound represented by the above general formula (XV)in the aforementioned production process, a compound wherein R¹ has anamide group represented by the following general formula (XVb) can bealso prepared by the following method:

wherein R⁹ represents a lower alkyl group having a substituent selectedfrom the following group (F);

-   (F) —COOR^(A9) or —CONR^(B4)R^(C4);    -   wherein R^(A9) represents a lower alkyl group;    -   R^(B4) and R^(C4) independently represent a hydrogen atom or a        lower alkyl group having —COOR^(B5) in which R^(B5) is a lower        alkyl group, with the proviso that both are not a hydrogen atom;        R¹⁰ represents a lower alkyl group having a substituent selected        from the following group (G);-   (G) —COOH or —CONR^(B6)R^(C6);    -   wherein R^(B6) and R^(C6) independently represent a hydrogen        atom or a lower alkyl group having —COOH, with the proviso that        both are not a hydrogen atom; and        R², R³, R^(A5), R^(A6), R^(B) and R^(C), —NR^(B)R^(c) and T have        the same meanings as defined above.        Process H

A compound represented by the above general formula (XVI) can behydrolyzed into a corresponding carboxylic acid compound represented bythe above general formula (XVa) by treating it with an acid such ashydrochloric acid or sulfuric acid at room temperature to refluxtemperature, or with a base such as sodium hydroxide in water and asolvent such as acetonitrile, tetrahydrofuran or alcohols usually at 0°C. to reflux temperature.

Process I

A compound represented by the above general formula (XVa) can beconverted into a corresponding amide compound represented by the abovegeneral formula (XVb) by allowing it to react with an amine compoundrepresented by the above general formula (VI) or a salt thereof, or anamine compound represented by the above general formula (VII) or a saltthereof in the presence of a condensing agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ordiphenylphosphoryl azide and in the presence or absence of an agent formaking an activated ester such as 1-hydroxybenzotriazole monohydrate anda base such as triethylamine in a solvent such as dichloromethane orN,N-dimethylformamide usually at 0° C. to room temperature.

In the aforementioned production process, for example, a compoundrepresented by the above general formula (XIV) can be also prepared bythe following method:

wherein X⁵ represents a bromine atom, a chlorine atom or an iodine atom;and R⁵, R⁷ and T¹ have the same meanings as defined above.Process J

A benzenesulfonamide derivative represented by the above general formula(XIV) can be prepared by condensing a benzenesulfonamide derivativerepresented by the above general formula (XII) with a halide compoundrepresented by the above general formula (XVII) in the presence of aborate such as bis(pinacolato)diboron and a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex a in a solvent such as dioxane usually at roomtemperature to reflux temperature.

For example, the compound represented by the above general formula (XV)in the aforementioned production process can be also prepared using acompound represented by the following general formula (XVIII) obtainedby a similar reaction according to the above Processes A, B, C and Jfrom a corresponding compound wherein R⁵ is a methoxymethyl grouprepresented by the above general formula (IX) as a starting material bythe following method:

wherein X⁶ represents a bromine atom, a chlorine atom or an iodine atom;and R¹, R², R⁵, T and T¹ have the same meanings as defined above.Process K

A compound represented by the above general formula (XVIII) can beconverted into a phenol compound or a thiophenol compound represented bythe above general formula (XVc) by treating it in the presence of anacid such as hydrochloric acid or sulfuric acid in a solvent such astetrahydrofuran or isopropanol, or a mixed solvent thereof usually at 0°C. to reflux temperature.

Process L

A corresponding O- or S-alkylated compound represented by the abovegeneral formula (XVd) can be prepared by condensing a compoundrepresented by the above general formula (XVc) with a halide compoundrepresented by the above general formula (XIX) in the presence of a basesuch as N,N-diisopropylethylamine, triethylamine or potassium carbonatea in a solvent such as N,N-dimethylformamide, tetrahydrofuran or ethanolusually at −20° C. to reflux temperature.

Process M

A compound wherein T¹ is a sulfur atom and R¹ is not a hydrogen atom ofa compound represented by the above general formula (XVd) can beconverted into a corresponding sulfonyl compound by treating it with anoxidizing agent such as Oxone (trademark) or m-chloroperbenzoic acid ina solvent such as acetone or dichloromethane, or a mixed solvent of suchsolvent with water usually at 0° C. to reflux temperature.

For example, the compound represented by the above general formula (V)in the aforementioned production process is commercially available orcan be prepared by methods described in literature or the like (MichaelFolkmann, Synthesis, 1159 (1990); Jose Alxander, J. Med. Chem., 318-322,31 (1988)).

In the aforementioned production processes, the term “hydroxy-protectivegroup” means a hydroxyl-protective group used generally in organicsynthesis, which is described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,THEODORA W. GREENE, PETER G. WUTS by JOHN WILEY & SONS, INC, such as abenzyl group, a methoxymethyl group, an acetyl group or the like.

The compounds of the present invention obtained by the above productionprocess can be easily isolated and purified by conventional separationmeans such as fractional recrystallization, precipitation, purificationusing column chromatography, solvent extraction and the like.

The 5-amidino-2-hydroxybenzenesulfonamide derivatives represented by theabove general formula (I) of the present invention can be converted intotheir pharmaceutically acceptable salts in the usual way. Examples ofthe such salts include acid addition salts with mineral acids (e.g.,hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid and the like), acid addition salts withorganic acids (e.g., formic acid, acetic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citricacid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalicacid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid,glutamic acid, aspartic acid and the like), salts with organic amines(e.g., morpholine, pyrrolidine, piperidine, piperazine, lysine and thelike), and salts with inorganic bases such as a sodium salt, a potassiumsalt and a calcium salt.

In addition, the compounds represented by the above general formula (I)of the present invention also include its hydrates and solvates withpharmaceutically acceptable solvents (e.g., ethanol).

Of the compounds represented by the above general formula (I) of thepresent invention, compounds having an asymmetric carbon atom exist intwo optical isomer forms of (R) configuration and (S) configuration.Either one of the isomers or a mixture thereof can be employed in thepresent invention. In the compounds represented by the above generalformula (I) of the present invention, when geometrical isomers ortautomers exist, the present invention includes all of the geometricalisomers and tautomers.

When the 5-amidino-2-hydroxybenzenesulfonamide derivatives representedby the above general formula (I) and pharmaceutically acceptable saltsthereof are employed in the practical treatment, they are administeredorally or parenterally in the form of appropriate pharmaceuticalcompositions such as tablets, powders, fine granules, granules,capsules, injections, solutions, adhesive preparations, ointments,inhalants, suppositories and the like.

These pharmaceutical compositions can be prepared by admixing with or bydiluting and dissolving with an appropriate pharmaceutical additive suchas excipients, disintegrators, binders, lubricants, diluents, buffers,isotonic agents, antiseptics, moistening agents, emulsifiers, dispersingagents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with pharmaceutically conventionalmethods. In case of the use in combination with the drugs other than the5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I), they can be prepared by formulate each activeingredient together or individually.

The dosage of the 5-amidino-2-hydroxybenzenesulfonamide derivativesrepresented by the above general formula (I) or pharmaceuticallyacceptable salts thereof is appropriately decided depending on the sex,age, body weight, degrees of symptoms and treatment of each patient,which is approximately within the range of from 1 to 5,000 mg per dayper adult human in case of oral administration and approximately withinthe range of from 0.01 to 500 mg per day per adult human in case ofparenteral administration such as injection, and the daily dose can bedivided into one to several doses per day. Also, in the case of the usein combination with the other drugs, the dosage of the5-amidino-2-hydroxybenzenesulfonamide derivatives represented by theabove general formula (I) or pharmaceutically acceptable salts thereofcan be decreased appropriately and occasionally depending on the dosageof the other drugs.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Test Examples, Reference Examples and Examples. However,the present invention is not limited thereto.

Test Example 1 Inhibitory Effect on Human Activated Blood CoagulationFactor Xa-Induced Human Mesangial Cell Proliferation

Normal human mesangial cells were seeded at 10000 cells/200 μL ofMesangial cell growth medium/well in 96-well plates, and cultured in CO₂incubator (37° C., O₂:CO₂=95:5). One day after seeding, cells wererinsed with Mesangial cell basal medium containing 0.5% bovine serumalbumin (not containing growth factors), and then replaced the mediumwith Mesangial cell basal medium containing 0.5% bovine serum albumin(not containing growth factors) which was containing human activatedcoagulation factor X (hereinafter referred to as FXa; Calbiochem) and atest compound of certain concentrations, and cultured for 111 hours inCO₂ incubator (37° C., O₂:CO₂=95:5). After cultivation, cells wererinsed with Hank's balanced salt solution at 250 μL/well, and frozenpreservation of the cells at −30° C. was carried out until themeasurement of the amount of DNAs for every plate. For measurement ofthe amount of DNAs, fluorescence intensity (measurement condition:excitation 480 nm; emission 520 nm) was estimated using CellProliferation Assay Kit (Molecular Probe). The results are shown inTable 1. Compound 33 inhibited human FXa-induced mesangial cellproliferation concentration-dependently. In addition, it is shown that *in the Table has a significant difference (p<0.05) compared with thegroup which was added FXa alone.

TABLE 1 Test compound Additive Additive amount of Fluorescence CompoundNo. amount (μM) FXa (nM) intensity — — — 186.8* — — 20 227.0 Compound 33 1 20 206.2 10 20 178.3*

Test Example 2 Inhibitory Effect on Development of Diabetic Nephropathyin db/db Mice (Spontaneously Diabetic Mice)

Six weeks old male db/db mice (20 individuals) and non-diabetic typedb/+m mice (10 individuals) were used. db/db Mice were divided into twogroups (each 10 individuals), a test compound suspended in a 0.5%methylcellulose solution was orally administrated at 100 mg/kg to onegroup (test compound group) twice a day. On the other hand, a 0.5%methylcellulose solution alone was orally administrated to another group(control group) and db/+m mice twice a day. After continuingadministration for 10 weeks, urine collection was performed for eachmouse using a metabolism cage for 24 hours. Insoluble substances incollected urine samples were removed by centrifugal separation. Theurine albumin/creatinine ratio which can be obtained by rectifying theurine albumin concentration by the urine creatinine concentration wasevaluated as the index of the urine protein excretion. In addition, theurine albumin/creatinine ratio was calculated based on the formulabelow.Urine albumin/creatinine ratio=Urine albumin concentration/Urinecreatinine concentration

Urine albumin concentration was measured using a Murine MicroalbuminureaELISA Kit (Exocell Icc.), and urine creatinine concentration wasmeasured using a commercial kit for creatinine (Wako). The results areshown in Table 2. Compound 48 inhibited urine albumin excretionsignificantly. In addition, it is shown that * in the Table has asignificant difference (p<0.05) compared with control group.

TABLE 2 Urine albumin/ Compound No. Type of mouse creatinine ratio —db/+m 0.026* — db/db 0.386 Compound 48 db/db 0.202*

Test Example 3 Inhibitory Effect on Hypercoagulable State in db/db Mice(Spontaneously Diabetic Mice)

Thirty two weeks old male db/db mice (11 individuals) and wild type+m/+m mice (6 individuals) were used. db/db Mice were divided into twogroups, a 0.5% methylcellulose solution containing a test compound at100 mg/kg was orally administrated to one group (test compound group, 6individuals). On the other hand, a 0.5% methylcellulose solution alonewas orally administrated to another group (control group, 5 individuals)and +m/+m mice. One hour after administration, mice were anesthetizedwith diethyl ether. The blood was collected from the inferior vena cava,and the citrate plasma was obtained by centrifugal separation. Plasmathrombin-antithrombin III complex (TAT) level was measured using an EIA(enzyme immunoassay) kit (Dade behring). The result is shown in Table 3.Compound 48 decreased plasma TAT level significantly. In addition, it isshown that * in the Table has a significant difference (p<0.05) comparedwith control group.

TABLE 3 Plasma thrombin- antithrombin III Compound No. Type of mousecomplex level — +m/+m 5.98* — db/db 69.25 Compound 48 db/db 8.31*

Test Example 4 Acute Toxicity Test

Male ICR mice aged 7 weeks (SLC) were divided into several groupsconsisting of 5 mice. A solution containing a test compound was preparedto have an the administration volume of 50 mg/10 mL/kg (Method A) or 100mg/10 mL/kg (Method B). The solution was administered through the tailvein at an infusion rate of 1 mL/minute. Observations were performed atconstant interval, and the survival rate was judged for 24 hours. Theresults were shown as Table 4, and no death of mice was observed.

TABLE 4 Compound No. Method Number of death Compound 33 B 0/5 Compound47 A 0/5 Compound 47 B 0/5

Reference Example 1 7-Hydroxycroman-2-one

A mixture of 100 g of 7-hydroxycroman-2-one, 10 g of 10% palladium oncarbon, 500 mL of tetrahydrofuran and 800 mL of ethanol was stirredunder a hydrogen atmosphere at 65° C. for 15 hours. To the reactionmixture were added a suspension of 10 g of 10% palladium on carbon in200 mL of ethanol under ice-cooling, and the mixture was stirred under ahydrogen atmosphere at 65° C. for 15 hours. The reaction mixture wasfiltered through a diatomaceous earth, and the filtrate was concentratedunder reduced pressure to give 106.5 g of colorless7-hydroxycroman-2-one.

¹H-NMR (CDCl₃) δ ppm:

2.75-2.96 (4H, m), 5.81 (1H, br s), 6.59-6.66 (2H, m), 7.04 (1H, d,J=7.9 Hz)

Reference Example 2 7-Benzyloxycroman-2-one

To a stirred suspension of 202.4 g of 7-hydroxycroman-2-one and 341.0 gof potassium carbonate in N,N-dimethylformamide was added 153.2 mL ofbenzyl chloride at room temperature, and the mixture was stirred at roomtemperature for 15 hours. After the reaction mixture was concentratedunder reduced pressure to remove the solvent, the residue was added to amixture of ethyl acetate and water. The organic layer was separated,washed with water, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated under reduced pressure, and the residuewas triturated in diisopropyl ether-hexane. The solid was collected byfiltration to give 266.1 g of 7-benzyloxycromae-2-one as a pale brownsolid.

¹H-NMR (CDCl₃) δ ppm:

2.73-2.81 (2H, m), 2.90-2.98 (2H, m), 5.05 (2H, s), 6.68 (1H, d, J=2.5Hz), 6.73 (1H, dd, J=8.3, 2.5 Hz), 7.08 (1H, d, J=8.3 Hz), 7.30-7.46(5H, m)

Reference Example 3 3-(4-Benzyloxy-2-hydroxyphenyl)propionamide

To a solution of 33.26 g of 7-benzyloxycroman-2-one in 264 mL oftetrahydrofuran was added 82 mL of 28% aqueous ammonia solution at roomtemperature. After the mixture was stirred at room temperature for 20minutes, to the reaction mixture was added 654 mL of 1 mol/Lhydrochloric acid in an ice-bath. The resulted suspension was dilutedwith about 1 L of water, and the precipitate was collected by filtrationto give 34.8 g of 3-(4-benzyloxy-2-hydroxyphenyl)propionamide as acolorless powder.

¹H-NMR (CDCl₃) δ ppm:

2.60-2.70 (2H, m), 2.80-2.90 (2H, m), 5.01 (2H, s), 5.46 (2H, br s),6.49 (1H, dd, J=8.5, 2.5 Hz), 6.58 (1H, d, J=2.5 Hz), 6.93 (1H, d, J=8.5Hz), 7.28-7.45 (5H, m), 8.67 (1H, s)

Reference Example 4 3-(4-Benzyloxy-2-methoxymethoxyphenyl)propionamide

To a stirred suspension of 5.64 g of 60% sodium hydride in oil in 628 mLof N,N-dimethylformamide was added 34.8 g of3-(4-benzyloxy-2-hydroxyphenyl)propionamide under ice-cooling, and themixture was stirred at 50° C. for 40 minutes. To the reaction mixturewas added 12.39 g of chloromethyl methyl ether under ice-cooling, andthe mixture was stirred at room temperature for 15 hours. After thereaction mixture was concentrated under reduced pressure to remove thesolvent, the residue was poured into a mixture of 500 mL of ethylacetate, 100 mL of toluene, and 200 mL of water. The organic layer wasseparated, washed with water, dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated under reduced pressure togive a colorless solid. The solid was triturated in ethylacetate-diisopropyl ether to collect by filtration of 35.3 g of3-(4-benzyloxy-2-methoxymethoxyphenyl)propionamide as a colorless solid.

¹H-NMR (CDCl₃) δ ppm:

2.50 (2H, t, J=7.6 Hz), 2.91 (2H, t, J=7.6 Hz), 3.47 (3H, s), 5.02 (2H;s), 5.18 (2H, s), 5.25-5.45 (2H, m), 6.56 (1H, dd, J=8.5, 2.5 Hz), 6.77(1H, d, J=2.-5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.30-7.45 (5H, m)

Reference Example 5 2-(4-Benzyloxy-2-methoxymethoxyphenyl)ethylamine

To a solution of 28.42 g of3-(4-benzyloxy-2-methoxymethoxyphenyl)propionamide and 40.4 mL of1,8-diazabicyclo[5.4.0]-7-undecene in 895 mL of methanol was added 16.04g of N-bromosuccinimide at 65° C. After the mixture was stirred at 65°C. for 15 minutes, to the reaction mixture was added additional 16.04 gof N-bromosuccinimide at 65° C. After being stirred at 65° C. for 15minutes, the resulted mixture was concentrated under reduced pressure toremove the solvent. To the residue were added water and ethyl acetate,and the organic layer was separated. The organic layer was washed withwater, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give oily product.To a solution of this residue in 242 mL of ethanol was added 67.6 mL of8 mol/L aqueous potassium hydroxide solution, and the mixture wasrefluxed for 15 hours. The reaction mixture was concentrated underreduced pressure to remove the solvent. To the residue were added 500 mLof ethyl acetate, 50 mL of toluene, and 300 mL of water, and the organiclayer was separated. The organic layer was washed with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by medium pressureliquid column chromatography on silica gel (eluent: hexaneethyl acetate)to give 80.0 g of 2-(4-benzyloxy-2-methoxymethoxyphenyl)ethylamine as acolorless oil.

¹H-NMR (CDCl₃) δ ppm:

1.31 (2H, br s), 2.71 (2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz), 3.47(3H, s), 5.03 (2H, s), 5.17 (2H, s), 6.56 (1H, dd, J=8.2, 2.5 Hz), 6.79(1H, d, J=2.5 Hz), 7.04 (1H, d, J=8.2 Hz), 7.29-7.45 (5H, m)

Reference Example 6 4-(2-Aminoethyl)-3-methoxymethoxyphenol

A mixture of 18.00 g of2-(4-benzyloxy-2-methoxymethoxyphenyl)ethylamine, 3.6 g of 10% palladiumon carbon (Degussa Inc.: E101 NE/W) and 230 mL of ethanol was stirredunder a hydrogen atmosphere at room temperature for 1 hour. After thecatalyst was filtered off through a diatomaceous earth, the filtrate wasconcentrated under reduced pressure to give 12.65 g of4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.

¹H-NMR (CD₃OD) δ ppm:

2.65-2.75 (2H, m), 2.75-2.85 (2H, m), 3.45 (3H, s), 5.16 (2H, s), 6.36(1H, dd, J=8.1, 2.3 Hz), 6.58 (1H, d, J=2.3 Hz), 6.94 (1H, d, J=8.1 Hz)

Reference Example 7 N-Cyanomethyl-2,2,2-trifluoroacetamide

Aminoacetonitrile hydrogen sulfate (50 g) and 77 mL of pyridine weresuspended in 300 mL of dichloromethane, and 80 mL of trifluoroaceticanhydride was added to the stirred mixture under ice-cooling. After themixture was stirred at room temperature for 29 hours, the insolublematerial was removed by filtration, and washed with ethyl acetate. Afterthe filtrate was concentrated under reduced pressure, to the residue wasadded water. The mixture was extracted with ethyl acetate, and theorganic layer was washed with diluted hydrochloric acid and water. Afterthe extract was dried over anhydrous magnesium sulfate, the solvent wasremoved under reduced pressure to give 66 g ofN-cyanomethyl-2,2,2-trifluoroacetamide.

¹H-NMR (CDCl₃) δ ppm:

4.31 (2H, d, J=6.6 Hz), 7.10 (1H, br s)

Reference Example 82,2,2-Trifluoro-N-[2-(2-hydroxy-4-isopropylphenyl)-2-oxoethyl]acetamide

To 250 mL of 1.0 mol/L boron trichloride dichloromethane solution wereadded a solution of 28.5 mL of 3-isopropylphenol in 130 mL ofdichloromethane, 38 g of N-cyanomethyl-2,2,2-trifluoroacetamide and 14.2g of aluminum chloride under an argon atmosphere in an ice-bath withstirring. After the mixture was stirred at room temperature for 16hours, ice and 2 mol/L hydrochloric acid were added to the reactionmixture under ice-cooling. After the mixture was stirred at roomtemperature for 40 minutes, the organic layer was separated, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, washed with brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure, and 100 mL ofhexane was added to the residue. The generated crystal was collected byfiltration, washed with hexane and dried under reduced pressure to give22.9 g of2,2,2-trifluoro-N-[2-(2-hydroxy-4-isopropylphenyl)-2-oxoethyl]acetamide.

¹H-NMR (CDCl₃) δ ppm:

1.26 (6H, d, J=8.8 Hz), 2.86-2.98 (1H, m), 4.83 (2H, d, J=4.1 Hz), 6.85(1H, dd, J=8.2, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 7.42 (1H, br s), 7.59(1H, d, J=8.2 Hz), 11.42 (1H, br s)

Reference Example 9Ethyl[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]-phenoxy]acetate

To a solution of 500 mg of2,2,2-trifluoro-N-[2-(2-hydroxy-4-isopropylphenyl)-2-oxoethyl]acetamidein 2.63 mL of trifluoroacetic acid was added 0.94 mL of triethylsilane.After being stirred at room temperature for 13 hours, the reactionmixture was concentrated and dried thoroughly. The obtained residue and382 mg of potassium carbonate were suspended in 10 mL ofN,N-dimethylformamide, and 0.288 mL of ethyl bromoacetate was added tothe stirred mixture under ice-cooling. The mixture was stirred at roomtemperature for 15 hours, and to the reaction mixture was added water.After the mixture was extracted with ethyl acetate, the organic layerwas washed successively with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe obtained residue was purified by column chromatography on silica gel(eluent: ethyl acetate-hexane) to give 535 mg ofethyl[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]phenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm:

1.10-1.30 (9H, m), 2.75-2.95 (3H, m), 3.35-3.50 (2H, m), 4.17 (2H, q,J=7.3 Hz), 4.81 (2H, s), 6.70-6.90 (2H, m), 7.03 (1H, d, J=7.5 Hz),9.40-9.55 (1H, m)

Reference Example 10

The following compound was prepared according to a similar manner tothat described in Reference Example 9.

Ethyl 2-[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]phenoxy]propionate ¹H-NMR (CDCl₃) δ ppm:

1.18-1.22 (6H, m), 1.25 (3H, t, J=6.9 Hz), 1.64 (3H, d, J=6.6 Hz),2.79-2.93 (2H, m), 2.95-3.02 (1H, m), 3.55-3.64 (1H, m), 3.68-3.76 (1H,m), 4.21 (2H, q, J=6.9 Hz), 4.88 (1H, q, J=6.6 Hz), 6.59-6.61 (1H, m),6.79-6.83 (1H, m), 7.05 (1H, d, J=7.3 Hz), 7.16 (1H, br s)

Reference Example 11 Ethyl[2-(2-aminoethyl)-5-isopropylphenoxy]acetatehydrochloride

To a solution of 26.4 g ofethyl[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]phenoxy]acetatein a mixture of 300 mL of methanol and 15 mL of water was added 30.3 gof potassium carbonate. After the mixture was stirred at roomtemperature for 20 hours, the insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure. Tothe residue was added 300 mL of 35% hydrogen chloride ethanol solution,and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure to give a crudeproduct of 24.8 g of ethyl[2-(2-aminoethyl)-5-isopropylphenoxy]acetatehydrochloride.

¹H-NMR (DMSO-d₆ ppm:

1.17 (6H, d, J=6.9 Hz), 1.21 (3H, t, J=7.3 Hz), 2.75-2.95 (3H, m),2.95-3.05 (2H, m), 4.18 (2H, q, J=7.3 Hz), 4.84 (2H, s), 6.75-6.79 (1H,m), 6.81 (1H, dd, J=7.9, 1.6 Hz), 7.10 (1H, d, J=7.9 Hz), 8.13 (3H, brs)

Reference Example 12

The following compound was prepared according to a similar manner tothat described in Reference Example 11.

Ethyl 2-[2-(2-aminoethyl)-5-isopropylphenoxy]propionate hydrochloride

¹H-NMR (CDCl₃) δ ppm:

1.12-1.19 (9H, m), 1.54 (3H, d, J=6.5 Hz), 2.75-3.11 (5H, m), 4.09-4.18(2H, m), 5.06 (1H, q, J=6.5 Hz), 6.71 (1H, s), 6.78-6.82 (1H, m), 7.09(1H, d, J=8.0 Hz), 7.93 (3H, br s)

Reference Example 13 2-Hydroxy-4-isopropylbenzaldehyde

To 100 mL of trifluoroacetic acid were added 25.39 g of3-isopropylphenol and 26.14 g of hexamethylenetetramine. After beingstirred at 60° C. for an hour, the reaction mixture was concentratedunder reduced pressure. To the residue was added diluted hydrochloricacid, and the mixture was stirred at room temperature for 30 minutes.After the reaction mixture was extracted with ethyl acetate, the organiclayer was washed with saturated aqueous sodium bicarbonate solution, andbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: ethyl acetate-hexane) to give 6.69g of 2-hydroxy-4-isopropylbenzaldehyde.

¹H-NMR (CDCl₃) δ ppm:

1.26 (6H, d, J=6.9 Hz), 2.92 (1H, sept, J=6.9 Hz), 6.83-6.87 (1H, m),6.88 (1H, dd, J=7.9, 1.6 Hz), 7.47 (1H, d, J=7.9 Hz), 9.83 (1H, s),11.03 (1H, br s)

Reference Example 14 2-Benzyloxy-4-isopropylbenzaldehyde

2-Hydroxy-4-isopropylbenzaldehyde (6.69 g) and 11.26 g of potassiumcarbonate were suspended with 100 mL of N,N-dimethylformamide, and 5.33mL of benzyl bromide was added to the stirred mixture at roomtemperature. After the mixture was stirred at room temperature for 16hours, the insoluble material was removed by filtration. To the filtratewere added 10 mL of water and 10 mL of diluted hydrochloric acid, andthe mixture was extracted with ethyl acetate. After being washed withbrine, the organic layer was dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure, and the obtained residue waspurified by column chromatography on silica gel (eluent: ethylacetate-hexane) to give 10.44 g of 2-benzyloxy-4-isopropylbenzaldehyde.

¹H-NMR (CDCl₃) δ ppm:

1.25 (6H, d, J=6.9 Hz), 2.88-2.97 (1H, m), 5.19 (2H, s), 6.90 (1H, s),6.92 (1H, d, J=7.9 Hz), 7.32-7.47 (5H, m), 7.79 (1H, d, J=7.9 Hz), 10.49(1H, s)

Reference Example 15 2-Benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene

To 100 mL of nitromethane were added 10.44 g of2-benzyloxy-4-isopropylbenzaldehyde and 4.71 g of ammonium acetate.After being stirred at external 100° C. for 3 hours, the reactionmixture was concentrated under reduced pressure. The obtained residuewas dissolved in ethyl acetate, and the organic layer was washedsuccessively with 1 mol/L hydrochloric acid, and saturated aqueoussodium bicarbonate solution, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure to give 9.45 g of2-benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene.

¹H-NMR (CDCl₃) δ ppm:

1.24 (6H, d, J=7.3 Hz), 2.87-2.95 (1H, m), 5.21 (2H, s), 6.86-6.93 (2H,m), 7.33-7.48 (6H, m), 7.82 (1H, d, J=13.2 Hz), 8.15 (1H, d, J=13.2 Hz)

Reference Example 16 2-(2-Benzyloxy-4-isopropylphenyl)ethylamine

To a stirred suspension of 3.01 g of lithium aluminum hydride in 100 mLof anhydrous diethyl ether was added dropwise a solution of 9.45 g of2-benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene in 10 mL of diethylether under ice-cooling with stirring during 10 minutes. After themixture was stirred for 1 hour, 63.5 mL of 2 mol/L sodium hydroxidesolution was added dropwise to the stirred reaction mixture underice-cooling, and the mixture was stirred for 1 hour. To the mixture wasadded anhydrous sodium sulfate, and the mixture was stirred for 15minutes. The insoluble material was filtered off through a diatomaceousearth, and 100 mL of water was added to the filtrate. The mixture wasextracted with ethyl acetate, and the organic layer was washedsuccessively with saturated aqueous sodium bicarbonate solution, andbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give 8.56 g of2-(2-benzyloxy-4-isopropylphenyl)ethylamine.

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 2.80 (2H, t, J=6.9 Hz), 2.83-2.91 (1H, m), 2.96(2H, t, J=6.9 Hz), 5.07 (2H, s), 6.76-6.80 (2H, m), 7.08 (1H, d, J=7.3Hz), 7.29-7.47 (5H, m)

Reference Example 17 tert-ButylN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate

To 100 mL of tetrahydrofuran were added 8.56 g of2-(2-benzyloxy-4-isopropylphenyl)ethylamine and 7.63 g of di-tert-butyldicarbonate, and the mixture was stirred at room temperature for 12hours. The solvent was removed under reduced pressure, and the obtainedresidue was purified by column chromatography on silica gel (eluent:ethyl acetate-hexane) to give 12.00 g of tert-butylN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate.

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 1.41 (9H, s), 2.76-2.91 (3H, m), 3.27-3.42 (2H,m), 4.69 (1H, br s), 5.08 (2H, s), 6.75-6.82 (2H, m), 7.07 (1H, d, J=7.9Hz), 7.30-7.48 (5H, m)

Reference Example 18 tert-ButylN-[2-(2-hydroxy-4-isopropylphenyl)ethyl]carbamate

tert-Butyl N-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate (12.00 g)was dissolved in 150 mL of ethanol. To the stirred solution was added1.10 g of 10% palladium on carbon under ice-cooling, and the mixture wasstirred under a hydrogen atmosphere and ordinary pressure at 30° C. for16 hours. The insoluble material was filtered, and the filtrate wasconcentrated under reduced pressure to give 6.66 g of tert-butylN-[2-(2-hydroxy-4-isopropylphenyl)ethyl]carbamate.

¹H-NMR (CDCl₃) δ ppm:

1.21 (6H, d, J=6.9 Hz), 1.45 (9H, s), 2.75-2.86 (3H, m), 3.25-3.32 (2H,m), 4.92 (1H, br s), 6.65-6.71 (1H, m), 6.72-6.75 (1H, m), 6.96 (1H, d,J=7.9 Hz), 7.03 (1H, brs)

Reference Example 19 Ethyl4-[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenoxy]butyrate

tert-Butyl N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]carbamate (0.234 g)and 0.116 g of potassium carbonate were suspended in 5 mL ofN,N-dimethylformamide. To the stirred suspension was added dropwise0.126 mL of ethyl 4-bromobutyrate at room temperature, and the mixturewas stirred at room temperature for 16 hours. To the reaction mixturewere added 10 mL of 1 mol/L hydrochloric acid and then 20 mL of water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure, and the obtained residue waspurified by column chromatography on silica gel (eluent: ethylacetate-hexane) to give 0.283 g of ethyl4-[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenoxy]butyrate.

¹H-NMR (CDCl₃) δ ppm:

1.24 (6H, d, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.42 (9H, s), 2.10-2.19(2H, m), 2.53 (2H, t, J=7.3 Hz), 2.72-2.79 (2H, m), 2.81-2.89 (1H, m),3.28-3.38 (2H, m), 4.02 (2H, t, J=6.0 Hz), 4.15 (2H, q, J=7.3 Hz), 4.75(1H, br s), 6.68-6.71 (1H, m), 6.74-6.79 (1H, m), 7.04 (1H, d, J=7.6 Hz)

Reference Example 20 Ethyl4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride

4-[2-(2-tert-Butoxycarbonylaminoethyl)-5-isopropylphenoxy]-butyrate(0.283 g) was dissolved in 10 mL of 35% hydrogen chloride ethanolsolution, and the mixture was stirred at room temperature for 5 hours.The solvent was removed under reduced pressure to give 0.235 g of ethyl4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.18 (3H, t, J=6.9 Hz), 1.19 (6H, d, J=6.9 Hz), 1.94-2.04 (2H, m),2.78-2.89 (3H, m), 2.90-2.99 (2H, m), 4.01 (2H, t, J=6.3 Hz), 4.08 (2H,q, J=6.9 Hz), 6.75-6.79 (1H, m), 6.81-6.85 (1H, m), 7.07 (1H, d, J=7.6Hz), 7.93 (3H, br s)

Reference Example 21 2-(2-Benzyloxy-4-isopropylphenyl)ethylaminehydrochloride

To a solution of 0.300 g of tert-butylN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate in 2 mL of ethanolwas added 2 mL of 21% hydrogen chloride ethanol solution at roomtemperature. After being stirred at the same temperature for 2 hours,the reaction mixture was concentrated under reduced pressure to give0.261 g of 2-(2-benzyloxy-4-isopropylphenyl)ethylamine hydrochloride.

¹H-NMR (CDCl₃) δ ppm:

1.20 (6H, d, J=6.9 Hz), 2.78-2.87 (1H, m), 3.04-3.12 (2H, m), 3.15-3.25(2H, m), 5.10 (2H, s), 6.74 (1H, d, J=7.6 Hz), 6.78 (1H, s), 7.14 (1H,d, J=7.6 Hz), 7.33-7.48 (4H, m), 8.25 (3H, br s)

Reference Example 22 5-Carbamoyl-2-methoxybenzenesulfonyl chloride

To 1733 g of chlorosulfonic acid was added in small portions 150 g of4-methoxybenzamide under ice-cooling with stirring during 15 minutes,and the mixture was stirred at room temperature for 14 hours. Afterbeing stirred at 50° C. for additional 1.5 hours, the reaction mixturewas dropped into 7 kg of ice. The precipitate was collected byfiltration, washed with water and hexane to give 230 g of5-carbamoyl-2-methoxybenzenesulfonyl chloride.

¹H-NMR (DMSO-d₆ ppm:

3.81 (3H, s), 7.00 (1H, d, J=8.5 Hz), 7.10 (1H, br s), 7.84 (1H, dd,J=8.5, 2.5 Hz), 7.87 (1H, br s), 8.23 (1H, d, J=2.5 Hz)

Reference Example 23 5-Cyano-2-methoxybenzenesulfonyl chloride

5-Carbamoyl-2-methoxybenzenesulfonyl chloride (150 g) was suspended in1800 mL of ethyl acetate. After 219 mL of thionyl chloride was droppedto the stirred suspension under ice-cooling, 2.3 mL ofN,N-dimethylformamide was added to the mixture. After being stirred at55° C. for 3 hours, the reaction mixture was concentrated under reducedpressure. To the residue were added ethyl acetate and water, and theseparated organic layer was washed with water, saturated aqueous sodiumbicarbonate solution, and brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure, and theobtained crude product was recrystallized from ethyl acetate-hexane togive 86.8 g of 5-cyano-2-methoxybenzenesulfonyl chloride.

¹H-NMR (CDCl₃) δ ppm:

4.16 (3H, s), 7.24 (1H, d, J=8.8 Hz), 7.96 (1H, dd, J=8.8, 2.2 Hz), 8.28(1H, d, J=2.2 Hz)

Reference Example 24 2-(Methylthio)phenylboronic acid

Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and tothe suspension were added 3.00 g of 2-bromothioanisole and about 20 mgof iodine. After the reaction was started by heating employing a dryer,72 g of 2-bromothioanisole was dropped to the mixture during 20 minutes.After being heated for 1 hour, the reaction mixture was diluted with1000 mL of tetrahydrofuran, and cooled to 0° C. To the mixture was added102 mL of triisopropyl borate at the same temperature, and the mixturewas stirred at room temperature for 4 hours. To the reaction mixture wasadded water, and the solvent was removed under reduced pressure. Theresidue was added 500 mL of 2 mol/L hydrochloric acid, and the mixturewas extracted with 300 mL of diethyl ether. The organic layer wasextracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, andthe aqueous layer was acidified by addition of concentrated hydrochloricacid under ice-cooling. The residual diethyl ether was removed underreduced pressure, and the precipitate was collected by filtration togive 45.95 g of 2-(methylthio)phenylboronic acid.

¹H-NMR (DMSO-d₆) δ ppm:

2.50 (3H, s), 6.21-6.29 (2H, br s), 7.34 (1H, td, J=7.3, 1.3 Hz), 7.42(1H, td, J=7.3, 1.3 Hz), 7.52 (1H, dd, J=7.3, 1.3 Hz), 8.01 (1H, dd,J=7.3, 1.3 Hz)

Reference Example 25 Hydroxylammonium Acetate

To 100 mL of 50% aqueous hydroxylamine solution was added slowly 86.6 mLof acetic acid under ice-cooling with stirring, and the mixture wasstirred at the same temperature for 40 minutes, then at room temperaturefor 40 minutes. After the reaction mixture was concentrated underreduced pressure, the residue was dissolved in 50 mL of ethanol, and thesolution was concentrated under reduced pressure. To the residue wasadded toluene, and the mixture was concentrated under reduced pressure,and dried to give 76.4 g of hydroxylammonium acetate as a colorlesssolid.

¹H-NMR (DMSO-d₆) δ ppm:

1.88 (3H, s), 7.63 (4H, br s)

Reference Example 265-Cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzenesulfonamide

4-(2-Aminoethyl)-3-methoxymethoxyphenol (12.3 g) and 7.9 g of sodiumbicarbonate were suspended in a mixture of 133 mL of tetrahydrofuran and14.4 mL of water, to the suspension was added 18 mL portions of asolution of 14.50 g of 5-cyano-2-methoxybenzenesulfonyl chloride in 180mL of tetrahydrofuran every 10 minutes while the internal temperaturewas kept at 10-20° C. After being stirred at room temperature for 8hours, the reaction mixture was purified by column chromatography onaminopropylated silica gel (eluent: ethyl acetate), and recrystallizedfrom ethyl acetate-diisopropyl ether to give 21.87 g of5-cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzenesulfonamideas a colorless crystal.

¹H-NMR (CDCl₃) δ ppm:

2.74 (2H, t, J=6.3 Hz), 3.10-3.20 (2H, m), 3.40 (3H, s), 3.81 (3H, s),4.85-4.95 (2H, m), 5.08 (2H, s), 6.38 (1H, dd, J=8.2, 2.2 Hz), 6.59 (1H,d, J=2.2 Hz), 6.87 (1H, d, J=8.2 Hz), 7.00 (1H, d, J=8.5 Hz), 7.78 (1H,dd, J=8.5, 2.2 Hz), 8.16 (1H, d, J=2.2 Hz)

Reference Example 27Ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate

To a stirred solution of 326 mg ofethyl[2-(2-aminoethyl)-5-isopropylphenoxy]acetate hydrochloride and0.452 mL of triethylamine in a mixture of 10 mL of tetrahydrofuran and 5mL of water was added 238 mg of 5-cyano-2-methoxybenzenesulfonylchloride under ice-cooling, and the mixture was stirred at roomtemperature for 6 hours. To the reaction mixture was added 30 mL ofwater, and the mixture was extracted with 120 mL of ethyl acetate. Theorganic layer was washed with 100 mL of water, and 100 mL of brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: ethyl acetate-hexane) to give 343 mg ofethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (6H, d, J=6.9 Hz), 1.19 (3H, t, J=7.3 Hz), 2.60-2.70 (2H, m), 2.78(1H, sept, J=6.9 Hz), 3.02-3.07 (2H, m), 3.94 (3H, s), 4.15 (2H, q,J=7.3 Hz), 4.70 (2H, s), 6.65 (1H, d, J=1.7 Hz), 6.71 (1H, dd, J=7.6,1.7 Hz), 6.95 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.5 Hz), 7.49 (1H, brs), 8.00-8.10 (2H, m)

Reference Example 28

The following compounds were prepared according to a similar manner tothat described in Reference Example 26 or 27.

Ethyl4-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]butyrate

¹H-NMR (CDCl₃) δ ppm:

1.22 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.3 Hz), 2.01-2.09 (2H, m), 2.44(2H, t, J=7.3 Hz), 2.76 (2H, t, J=6.6 Hz), 2.80-2.90 (1H, m), 3.11-3.19(2H, m), 3.79 (3H, s), 3.94 (2H, t, J=6.0 Hz), 4.16 (2H, q, J=7.3 Hz),4.99 (1H, t, J=5.7 Hz), 6.64-6.68 (1H, m), 6.71-6.76 (1H, m), 6.94 (1H,d, J=7.6 Hz), 6.99 (1H, d, J=8.8 Hz), 7.78 (1H, dd, J=8.8, 2.2 Hz), 8.20(1H, d, J=2.2 Hz)

N-[2-(2-Benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 2.76-2.91 (3H, m), 3.14-3.21 (2H, m), 3.66 (3H,s), 4.85-4.91 (1H, m), 4.98 (2H, s), 6.74-6.79 (2H, m), 6.92 (1H, d,J=8.5 Hz), 6.97 (1H, d, J=8.2 Hz), 7.29-7.43 (5H, m), 7.73 (1H, dd,J=8.5, 1.9 Hz), 8.15 (1H, d, J=1.9 Hz)

Ethyl2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]propionate

¹H-NMR (CDCl₃) δ ppm:

1.16-1.22 (6H, m), 1.23-1.29 (3H, m), 1.57 (3H, d, J=6.8 Hz), 2.68-2.96(3H, m), 3.16-3.37 (2H, m), 3.73 (3H, s), 4.15-4.24 (2H, m), 4.77 (1H,q, J=6.8 Hz), 5.26 (1H, t, J=5.7 Hz), 6.51-6.53 (1H, m), 6.72-6.76 (1H,m), 6.90 (1H, d, J=7.6 Hz), 6.98 (1H, d, J=8.6 Hz), 7.77 (1H, dd, J=8.6,3.2 Hz), 8.30 (1H, d, J=3.2 Hz)

Reference Example 294-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate

To a stirred solution of 21.87 g of5-cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzenesulfonamideand 10.21 g of N,N-dimethylaminopyridine in 230 mL of dichloromethanewas added 9.38 mL of trifluoromethanesulfonic anhydride underice-cooling. The mixture was stirred for 1 hour, and about 50 g ofcrushed ice was added to the reaction mixture. The mixture wasconcentrated under reduced pressure to remove dichloromethane, and theresidue was poured into a mixture of 500 mL of ethyl acetate and 200 mLof water. The organic layer was separated, washed with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was recrystallized from ethylacetate-diisopropyl ether to give 24.75 g of4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate as a colorless powder.

¹H-NMR (CDCl₃) δ ppm:

2.86 (2H, t, J=6.6 Hz), 3.15-3.25 (2H, m), 3.44 (3H, s), 3.86 (3H, s),4.89 (1H, t, J=6.0 Hz), 5.16 (2H, s), 6.86 (1H, dd, J=8.5, 2.2 Hz),7.00-7.05 (2H, m), 7.12 (1H, d, J=8.5 Hz), 7.81 (1H, dd, J=8.5, 2.2 Hz),8.20 (1H, d, J=2.2 Hz)

Reference Example 305-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2′-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide

A mixture of 24.75 g of4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate, 8.32 g of 2-(methylthio)phenylboronic acid,2.73 g of tetrakis(triphenylphosphine)palladium(0), 728 mg oftetra-n-butylammonium bromide, 10.00 g of sodium carbonate, 48 mL ofwater and 285 mL of toluene was heated under an argon atmosphere at 85°C. for 15 hours. The precipitate was collected by filtration, washedsuccessively with ethyl acetate and water to give 19.74 g of5-cyano-2-methoxy-N-[2-(3-methoxymethoxy-2′-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamideas an yellow powder.

¹H-NMR (CDCl₃) δ ppm:

2.40 (3H, s), 2.88 (2H, t, J=6.3 Hz), 3.19-3.27 (2H, m), 3.43 (3H, s),3.82 (3H, s), 5.04 (1H, t, J=5.7 Hz), 5.17 (2H, s), 6.95-7.05 (2H, m),7.08 (1H, d, J=7.6 Hz), 7.10-7.25 (3H, m), 7.25-7.30 (1H, m), 7.30-7.40(1H, m), 7.79 (1H, dd, J=8.8, 2.2 Hz), 8.22 (1H, d, J=2.2 Hz)

Reference Example 31

The following compound was prepared according to a similar manner tothat described in Reference Example 30.

N-tert-Butyl-4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′-methoxymethoxybiphenyl-2-sulfonamide

¹H-NMR (CDCl₃) δ ppm:

1.01 (9H, s), 2.89 (2H, t, J=6.6 Hz), 3.23 (2H, m), 3.43 (3H, s), 3.79(1H, s), 3.96 (3H, s), 4.99 (1H, t, J=6.0 Hz), 5.22 (2H, s), 7.06 (1H,dd, J=7.6, 1.6 Hz), 7.09 (1H, d, J=8.8 Hz), 7.15 (1H, d, J=7.6 Hz),7.28-7.35 (2H, m), 7.49 (1H, td, J=7.6, 1.3 Hz), 7.57 (1H, td, J=7.6,1.3 Hz), 7.82 (1H, dd, J=8.8, 2.2 Hz), 8.17 (1H, dd, J=7.6, 1.3 Hz),8.22 (1H, d, J=2.2 Hz)

Reference Example 325-Cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxymethoxybiphenyl-4-yl)ethyl]benzenesulfonamide

A mixture of 10.0 g of4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate, 5.33 g of bis(pinacolato)diboron, 467 mg of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloridedichloromethane complex, 317 mg of1,1′-bis(diphenylphosphino)ferrocenepalladium(II), 5.61 g of potassiumacetate, and 113 mL of 1,4-dioxane was stirred under an argon atmosphereat 80° C. for 15 hours. To the reaction mixture were added 4.02 g of1-bromo-3,4,5-trifluorobenzene, 467 mg of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloridedichloromethane complex, 12.14 g of potassium phosphinate, and 40 mL of1,4-dioxane. The mixture was stirred under argon atmosphere at 80° C.for 24 hours, and ethyl acetate and water were added to the reactionmixture. The organic layer was separated, washed with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by columnchromatography on aminopropylated silica gel (eluent: ethylacetate-hexane) to give 10.09 g of5-cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxymethoxybiphenyl-4-yl)ethyl]benzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm:

2.87 (2H, t, J=6.6 Hz), 3.18-3.26 (2H, m), 3.46 (3H, s), 3.85 (3H, s),4.92 (1H, t, J=6.0 Hz), 5.21 (2H, s), 7.02 (1H, d, J=8.5 Hz), 7.06 (1H,dd, J=7.9, 1.6 Hz), 7.10-7.20 (4H, m), 7.79 (1H, dd, J=8.5, 2.2 Hz),8.20 (1H, d, J=2.2 Hz)

Reference Example 335-Cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamide

To a stirred suspension of 26.44 g of5-cyano-2-methoxy-N-[2-(3-methoxymethoxy-2′-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamideand 35.6 g of sodium bicarbonate in a mixture of 530 mL of acetone and106 mL of water was added two portions of 81.5 g of OXONE (trademark)every 15 minutes under ice-cooling. The mixture was stirred under thesame condition for 3 hours, and 100 mL of diethyl ether, 100 mL ofwater, and saturated aqueous sodium sulfate solution were added to thestirred reaction mixture under ice-cooling. The obtained mixture wasconcentrated under reduced pressure to remove acetone, and 300 mL ofwater, and diethyl ether-hexane were added to the stirred residue underice-cooling. The mixture was stirred for 30 minutes, and the precipitatewas collected by filtration, washed with water and diethyl ether-hexaneto give 27.1 g of5-cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamideas a white powder.

¹H-NMR (DMSO-d₆) δ ppm:

2.65-2.75 (2H, m), 2.79 (3H, s), 3.05-3.15 (2H, m), 3.30-3.35 (3H, m),4.00 (3H, s), 5.15 (2H, s), 6.94 (1H, dd, J=7.6, 1.6 Hz), 7.06 (1H, d,J=1.6 Hz), 7.16 (1H, d, J=7.6 Hz), 7.35-7.45 (2H, m), 7.66 (1H, td,J=7.6, 1.3 Hz), 7.70-7.80 (2H, m), 8.05-8.15 (3H, m)

Reference Example 345-Cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)-ethyl]-2-methoxybenzenesulfonamide

To a suspension of 14.89 g of5-cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamidein a mixture of 30 mL of isopropanol and 90 mL of tetrahydrofuran wasadded 11.7 mL of concentrated hydrochloric acid. After being stirred at50° C. for 2 hours, the reaction mixture was diluted with 50 mL ofwater, and extracted with 150 mL of ethyl acetate. The organic layer waswashed with saturated aqueous sodium bicarbonate solution, and brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on aminopropylated silica gel (eluent: ethylacetate-methanol) to give 10.22 g of5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamideas a colorless amorphous material.

¹H-NMR (CDCl₃) δ ppm:

2.69 (3H, s), 2.87 (2H, t, J=6.9 Hz), 3.20-3.30 (2H, m), 3.98 (3H, s),5.34 (1H, t, J=5.7 Hz), 5.93 (1H, s), 6.88 (1H, dd, J=7.6, 1.6 Hz), 6.97(1H, d, J=1.6 Hz), 7.05-7.15 (2H, m), 7.33 (1H, dd, J=7.6, 1.3 Hz), 7.56(1H, td, J=7.6, 1.3 Hz), 7.65 (1H, td, J=7.6, 1.3 Hz), 7.82 (1H, dd,J=8.5, 2.2 Hz), 8.15-8.25 (2H, m)

Reference Example 35

The following compounds were prepared according to a similar manner tothat described in Reference Example 34.

5-Cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-hydroxybiphenyl-4-yl)ethyl]-benzenesulfonamide

¹H-NMR (DMSO-d₆) δ ppm:

2.64 (2H, t, J=7.3 Hz), 3.07 (2H, t, J=7.3 Hz), 3.96 (3H, s), 6.93 (1H,d, J=1.9 Hz), 6.99 (1H, dd, J=7.6, 1.9 Hz), 7.05 (1H, d, J=7.6 Hz), 7.35(1H, d, J=8.5 Hz), 7.40-7.50 (2H, m), 7.95-8.05 (2H, m)

N-tert-Butyl4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′-hydroxybiphenyl-2-sulfonamide

¹H-NMR (CDCl₃) δ ppm:

1.00 (9H, s), 2.87 (2H, t, J=6.6 Hz), 3.23 (2H, m), 3.98 (3H, s), 5.28(1H, t, J=5.7 Hz), 6.10 (1H, s), 6.91 (1H, dd, J=7.6, 1.6 Hz), 7.06 (1H,d, J=1.6 Hz), 7.10 (1H, d, J=8.5 Hz), 7.13-7.20 (2H, m), 7.29 (1H, dd,J=7.6, 1.3 Hz), 7.48 (1H, td, J=7.6, 1.3 Hz), 7.56 (1H, td, J=7.6, 1.3Hz), 7.82 (1H, dd, J=7.6, 1.3 Hz), 8.14 (1H, dd, J=8.5, 2.2 Hz), 8.21(1H, d, J=2.2 Hz)

Reference Example 36

The following compound was prepared according to the similar manner tothat described in Reference Example 32 and 34.

Methyl4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′-hydroxybiphenyl-2-carboxylate

¹H-NMR (CDCl₃) δ ppm:

2.84 (2H, t, J=6.3 Hz), 3.20-3.30 (2H, m), 3.70 (3H, s), 3.90 (3H, s),5.53 (1H, t, J=5.4 Hz), 5.93 (1H, br), 6.67 (1H, d, J=1.6 Hz), 6.78 (1H,dd, J=7.9, 1.6 Hz), 7.00-7.05 (2H, m), 7.41 (1H, td, J=7.6, 1.3 Hz),7.51 (1H, td, J=7.6, 1.3 Hz), 7.73 (1H, dd, J=8.8, 2.2 Hz), 7.77 (1H,dd, J=7.6, 1.3 Hz), 8.21 (1H, d, J=2.2 Hz)

Reference Example 37Ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate

To a solution of 5.72 g of5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamidein 57 mL of N,N-dimethylformamide were added 2.46 mL ofN,N-diisopropylethylamine and 1.37 mL of ethyl bromoacetate. After beingstirred at 50° C. for 15 hours, and the reaction mixture was poured into100 mL of water, and extracted with a mixture of 150 mL of ethyl acetateand 20 mL of toluene. The organic layer was washed with water and brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on aminopropylated silica gel (eluent: ethylacetate-hexane) to give 2.96 g ofethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateas an amorphous material.

¹H-NMR (CDCl₃) δ ppm:

1.28 (3H, t, J=6.9 Hz), 2.59 (3H, s), 2.95 (2H, t, J=6.6 Hz), 3.30-3.60(2H, m), 3.99 (3H, s), 4.23 (2H, q, J=6.9 Hz), 4.68 (2H, s), 5.43 (1H,t, J=6.3 Hz), 6.95 (1H, dd, J=7.6, 1.6 Hz), 7.04 (1H, d, J=1.6 Hz), 7.09(1H, d, J=8.5 Hz), 7.20 (1H, d, J=7.6 Hz), 7.36 (1H, dd, J=7.6, 1.3 Hz),7.57 (1H, td, J=7.6, 1.3 Hz), 7.65 (1H, td, J=7.6, 1.3 Hz), 7.80 (1H,dd, J=8.5, 2.2 Hz), 8.20-8.25 (2H, m)

Reference Example 38

The following compounds were prepared according to a similar manner tothat described in Reference Example 37.

Ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetate

¹H-NMR (CDCl₃) δ ppm:

1.32 (3H, t, J=7.3 Hz), 2.92 (2H, t, J=6.6 Hz), 3.30 (2H, q, J=6.6 Hz),3.88 (3H, s), 4.27 (2H, q, J=7.3 Hz), 4.68 (2H, s), 5.26 (1H, t, J=6.6Hz), 6.78 (1H, d, J=1.6 Hz), 7.00-7.14 (4H, m), 7.16 (1H, d, J=7.6 Hz),7.78 (1H, dd, J=8.8, 2.2 Hz), 8.20 (1H, d, J=2.2 Hz)

Methyl4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′-ethoxycarbonylmethoxybiphenyl-2-carboxylate

¹H-NMR (CDCl₃) δ ppm:

1.29 (3H, t, J=6.9 Hz), 2.91 (2H, t, J=6.3 Hz), 3.25-3.35 (2H, m), 3.68(3H, s), 3.89 (3H, s), 4.25 (2H, q, J=6.3 Hz), 4.59 (2H, s), 5.33 (1H,t, J=6.0 Hz), 6.66 (1H, d, J=1.6 Hz), 6.88 (1H, dd, J=7.6, 1.6 Hz), 7.05(1H, d, J=8.5 Hz), 7.08 (1H, d, J=7.6 Hz), 7.30 (1H, dd, J=7.6, 1.3 Hz),7.42 (1H, td, J=7.6, 1.3 Hz), 7.53 (1H, td, J=7.6, 1.3 Hz), 7.75-7.85(2H, m), 8.22 (1H, d, J=2.2 Hz)

Ethyl[2′-tert-butylsulfamoyl-4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]biphenyl-3-yloxy]acetate

¹H-NMR (CDCl₃) δ ppm:

0.94 (9H, s), 1.31 (3H, t, J=7.3 Hz), 2.94 (2H, t, J=6.6 Hz), 3.32 (2H,m), 3.86 (1H, s), 3.99 (3H, s), 4.27 (2H, q, J=7.3 Hz), 4.72 (2H, s),5.28 (1H, t, J=6.3 Hz), 6.94 (1H, dd, J=7.6, 1.9 Hz), 7.08 (1H, d, J=8.8Hz), 7.22 (1H, d, J=1.3 Hz), 7.24 (1H, d, J=7.6 Hz), 7.33 (1H, dd,J=7.6, 1.3 Hz), 7.48 (1H, td, J=7.6, 1.3 Hz), 7.56 (1H, td, J=7.6, 1.3Hz), 7.81 (1H, dd, J=8.8, 2.2 Hz), 8.17 (1H, dd, J=7.6, 1.3 Hz), 8.21(1H, d, J=2.2 Hz)

Reference Example 39[2-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-aceticacid

To a solution of 4.52 g ofethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein ethanol was added 12.3 mL of 2 mol/L sodium hydroxide solution toneutralize. After being stirred at room temperature for 3 hours, thereaction mixture was concentrated, and 1 mol/L hydrochloric acid wasadded to the residue. After the mixture was extracted with ethylacetate, the organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 4.16 g of[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid.

¹H-NMR (CDCl₃) δ ppm:

1.22 (6H, d, J=6.3 Hz), 2.80-2.89 (3H, m), 3.18-3.24 (2H, m), 3.74 (3H,s), 4.68 (2H, s), 5.35 (1H, t, J=5.7 Hz), 6.58-6.62 (1H, m), 6.80 (1H,d, J=7.3 Hz), 6.97 (1H, d, J=7.3 Hz), 6.99 (1H, d, J=8.5 Hz), 7.30-8.10(2H, m), 8.18 (1H, d, J=2.2 Hz)

Reference Example 40

The following compound was prepared according to a similar manner tothat described in Reference Example 39.

4-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]aceticacid

¹H-NMR (DMSO-d₆) δ ppm:

2.71 (2H, t, J=7.3 Hz), 3.05-3.20 (2H, m), 3.93 (3H, s), 4.78 (2H, s),7.10-7.15 (2H, m), 7.19 (1H, dd, J=7.9, 1.6 Hz), 7.30-7.35 (1H, m),7.60-7.75 (3H, m), 8.00-8.05 (2H, m), 12.5-13.5 (1H, br)

Reference Example 41Ethyl[2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetylamino]acetate

To a stirred solution of 0.3 g of[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid, 0.107 g of glycine ethyl ester hydrochloride and 0.103 g of1-hydroxybenzotriazole monohydrate in N,N-dimethylformamide were added0.106 mL of triethylamine and 0.146 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride underice-cooling, and the mixture was stirred at room temperature for 15hours. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with 1 mol/Lhydrochloric acid, saturated aqueous sodium bicarbonate solution, waterand brine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the obtained residue was purified bycolumn chromatography on silica gel (eluent: ethyl acetatehexane) togive 0.33 g ofethyl[2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetylamino]acetate

¹H-NMR (CDCl₃) δ ppm:

1.22 (6H, d, J=7.3 Hz), 1.31 (3H, t, J=7.3 Hz), 2.80-3.00 (3H, m),3.17-3.24 (2H, m), 3.91 (3H, s), 4.16 (2H, d, J=5.5 Hz), 4.27 (2H, q,J=7.3 Hz), 4.53 (2H, s), 5.24 (1H, t, J==6.3 Hz), 6.68 (1H, d, J=1.1Hz), 6.83 (1H, dd, J=7.9, 1.1 Hz), 7.01 (1H, d, J=7.9 Hz), 7.05 (1H, d,J=8.4 Hz), 7.80 (1H, dd, J=8.4, 2.2 Hz), 8.21 (1H, d, J=2.2 Hz)

Reference Example 42

The following compound was prepared according to a similar manner tothat described in Reference Example 41.

Ethyl3-[2-[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]propionate

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.3 Hz), 2.78 (2H, t, J=6.9 Hz), 3.12 (2H, q, J=6.9 Hz),3.35-3.45 (2H, m), 3.93 (3H, s), 4.01 (2H, q, J=7.3 Hz), 4.59 (2H, s),7.10-7.20 (2H, m), 7.22 (1H, dd, J=7.9, 1.6 Hz), 7.34 (1H, d, J=8.5 Hz),7.61-7.66 (1H, m), 7.67-7.75 (2H, m), 7.87 (1H, t, J=6.0 Hz), 8.00-8.05(2H, m)

Reference Example 432-[2-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide

A mixture of 0.169 g of[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid, 41.8 mg of ammonium chloride, 79.2 mg of 1-hydroxybenzotriazolemonohydrate, 0.272 mL of N,N-diisopropylethylamine and 0.112 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride wasstirred at room temperature for 27 hours. The reaction mixture wasdiluted with water, and extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium bicarbonate solution and brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the obtained residue was purified by columnchromatography on aminopropylated silica gel (eluent:dichloromethane-ethyl acetate) to give 151.4 mg of2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide.

¹H-NMR (CDCl₃) δ ppm:

1.22 (6H, d, J=7.3 Hz), 2.83-2.92 (3H, m), 3.14-3.21 (2H, m), 3.90 (3H,s), 4.51 (2H, s), 5.21 (1H, br s), 5.87 (1H, br s), 6.70 (1H, d, J=1.3Hz), 6.80 (1H, br s), 6.82 (1H, dd, J=7.9, 1.3 Hz), 7.00 (1H, d, J=7.9Hz), 7.06 (1H, d, J=8.5 Hz), 7.81 (1H, dd, J=8.5, 1.9 Hz), 8.17 (1H, d,J=1.9 Hz)

Reference Example 44

The following compounds were prepared according to a similar manner tothat described in Reference Example 43.

2-[2-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-N,N-dimethylacetamide

¹H-NMR (CDCl₃) δ ppm:

1.22 (6H, d, J=6.9 Hz), 2.80-2.90 (3H, m), 2.99 (3H, s), 3.06 (3H, s),3.21-3.28 (2H, m), 3.80 (3H, s), 4.67 (2H, s), 5.71 (1H, t, J=6.0 Hz),6.64 (1H, d, J=1.3 Hz), 6.77 (1H, dd, J=7.6, 1.3 Hz), 6.95 (1H, d, J=7.6Hz), 6.99 (1H, d, J=8.5 Hz), 7.76 (1H, dd, J=8.5, 2.2 Hz), 8.18 (1H, d,J=2.2 Hz)

5-Cyano-N-[2-[4-isopropyl-2-(2-morpholin-4-yl-2-oxoethoxy)-phenyl]ethyl]-2-methoxybenzenesulfonamide

¹H-NMR (CDCl₃) δ ppm:

1.22 (6H, d, J=6.9 Hz), 2.79-2.90 (3H, m), 3.22 (2H, q, J=6.0 Hz),3.50-3.56 (2H, m), 3.60-3.72 (6H, m), 3.82 (3H, s), 4.68 (2H, s), 5.47(1H, t, J=6.0 Hz), 6.66 (1H, d, J=1.3 Hz), 6.79 (1H, dd, J=7.9, 1.3 Hz),6.96 (1H, d, J=7.9 Hz), 7.00 (1H, d, J=8.5 Hz), 7.77 (1H, dd, J=8.5, 2.2Hz), 8.18 (1H, d, J=2.2 Hz)

Reference Example 45 (4-Isopropylphenyl)acetonitrile

To a stirred solution of 100 g of 4-isopropylbenzyl chloride in 1500 mLof N,N-dimethylformamide was added 32.0 g of sodium cyanide underice-cooling. The mixture was stirred at 70° C. for 4 hours, and waterwas added to the reaction mixture. The mixture was extracted with ethylacetate, and the organic layer was washed with water and brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give 96.5 g of (4-isopropylphenyl)acetonitrile.

¹H-NMR (CDCl₃) δ ppm:

1.24 (6H, d, J=6.9 Hz), 2.91 (1H, sept, J=6.9 Hz), 3.70 (2H, s),7.22-7.27 (4H, m)

Reference Example 46 2-(4-Isopropylphenyl)ethylamine hydrochloride

To 1000 mL of 1.0 mol/L boran-tetrahydrofuran complex was added dropwisea solution of 79.6 g of (4-isopropylphenyl)acetonitrile in 400 mL oftetrahydrofuran under ice-cooling with stirring, and the mixture wasstirred at room temperature for 2 hours. To the stirred reaction mixturewas added 500 mL of methanol under ice-cooling during 30 minutes, andthe mixture was stirred at the same temperature for 20 minutes. Afterthe reaction mixture was concentrated under reduced pressure, to theresidue were added isopropanol and 500 mL of 2 mol/L hydrochloric acid.The solvent was removed under reduced pressure, and the residue wasrecrystallized from isopropanol-diisopropyl ether to give 41.5 g of2-(4-Isopropylphenyl)ethylamine hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.18 (6H, d, J=6.9 Hz), 2.81-2.92 (3H, m), 2.96-3.05 (2H, m), 7.14-7.26(4H, m), 8.05 (3H, br s)

Reference Example 472,2,2-Trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide

To a stirred solution of 2.59 g of 2-(4-isopropylphenyl)ethylamine in 10mL of N,N-dimethylformamide were added 4.0 mL of triethylamine and 1.95mL of trifluoroacetic anhydride under ice-cooling, and the mixture wasstirred at room temperature for an hour. To the reaction mixture wereadded water and 10 mL of 1 mol/L hydrochloric acid, and the mixture wasextracted three times with 20 mL of ethyl acetate. The organic layerswere combined and washed with water, saturated aqueous sodiumbicarbonate solution, and brine. The mixture was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.Hexane was added to the residue, and the crystal was collected byfiltration to give 2.39 g of2,2,2-trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide.

¹H-NMR (CDCl₃) δ ppm:

1.24 (6H, d, J=6.9 Hz), 2.79-2.96 (3H, m), 3.60 (2H, q, J=6.6 Hz), 6.33(1H, br s), 7.11 (2H, d, J=7.9 Hz), 7.20 (2H, d, J=7.9 Hz)

Reference Example 485-Isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]benzenesulfonylchloride

Chlorosulfonic acid (2.05 mL) was added to 1.6 g of2,2,2-trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide, and the mixturewas stirred at room temperature for 3 hours. The reaction mixture waspoured into ice-water, and water was added to the mixture. The mixturewas extracted with ethyl acetate, and the organic layer was washed withbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: ethyl acetate-hexane) to give0.463 g of5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]benzenesulfonylchloride.

¹H-NMR (CDCl₃) δ ppm:

1.30 (6H, d, J=6.9 Hz), 3.02 (1H, sept, J=6.9 Hz), 3.39 (2H, t, J=7.3Hz), 3.68-3.77 (2H, m), 6.66 (1H, br s), 7.42 (1H, d, J=7.9 Hz), 7.57(1H, dd, J=7.9, 1.9 Hz), 7.95 (1H, d, J=1.9 Hz)

Reference Example 49N-[2-(2-tert-Butylsulfamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamide

To a solution of 0.463 g of5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]benzenesulfonylchloride in 30 mL of tetrahydrofuran was added 0.500 mL oftert-butylamine. The mixture was sealed and stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and the residue was dissolved in 30 mL of water and 10 mL of 1 mol/Lhydrochloric acid. The mixture was extracted with ethyl acetate, and theorganic layer was washed with water, saturated aqueous sodiumbicarbonate solution, and brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure to give 0.481 g ofN-[2-(2-tert-butylsulfamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamide.

¹H-NMR (CDCl₃) δ ppm:

1.21-1.35 (15H, m), 2.90-3.05 (1H, m), 3.22-3.36 (2H, m), 3.61-3.75 (2H,m), 4.54-4.66 (1H, m), 7.32-7.49 (2H, m), 7.84-7.95 (1H, m)

Reference Example 502-(2-Aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide

To a solution of 0.481 g ofN-[2-(2-tert-butylsulfamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamidein 5 mL of ethanol was added 5 mL of 2 mol/L sodium hydroxide solution,and the mixture was allowed to stand at room temperature for 4 hours. Tothe reaction mixture was added 5 mL of 2 mol/L hydrochloric acid, andthe mixture was concentrated under reduced pressure. To the residue wasadded saturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure to give 0.288 g of2-(2-aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm:

1.20-1.28 (15H, m), 2.94 (1H, sept, J=6.9 Hz), 3.09 (2H, t, J=6.6 Hz),3.21 (2H, t, J=6.6 Hz), 7.23-7.28 (1H, m), 7.33 (1H, dd, J=7.9, 1.9 Hz),7.91 (1H, d, J=1.9 Hz)

Reference Example 513-[[2-(2-tert-Butylsulfamoyl-4-isopropylphenyl)ethyl]-sulfamoyl]-4-methoxybenzamide

To a suspension of 241 mg of 5-carbamoyl-2-methoxybenzenesulfonylchloride and 288 mg of2-(2-aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide in 10 mL ofN,N-dimethylformamide was added 0.32 mL of triethylamine, and themixture was stirred at room temperature for 3 days. To the reactionmixture was added 30 mL of water, and the mixture was stirred at thesame temperature for 1 hour. To the mixture was added 10 mL of 1 mol/Lhydrochloric acid, and the mixture was extracted three times with 20 mLof ethyl acetate. The organic layers were combined and washed with 30 mLof water, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give 426 mg of3-[[2-(2-tert-butylsulfamoyl-4-isopropylphenyl)ethyl]sulfamoyl]-4-methoxybenzamide.

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 1.25 (9H, s), 2.86-2.97 (1H, m), 3.13-3.20 (2H,m), 3.21-3.30 (2H, m), 3.99 (3H, s), 5.20 (1H, br s), 5.37 (1H, t, J=6.0Hz), 5.43-5.69 (1H, br), 6.60-6.88 (1H, br), 7.05 (1H, d, J=8.8 Hz),7.14 (1H, d, J=7.9 Hz), 7.25-7.30 (1H, m), 7.88 (1H, d, J=1.9 Hz), 8.13(1H, dd, J=8.8, 2.5 Hz), 8.32 (1H, d, J=2.5 Hz)

Reference Example 52N-tert-Butyl-2-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-5-isopropylbenzenesulfonamide

To a stirred solution of 420 mg of3-[[2-(2-tert-butylsulfamoyl-4-isopropylphenyl)ethyl]sulfamoyl]-4-methoxybenzamidein 30 mL of dichloromethane were added 0.48 mL of triethylamine and0.245 mg of trifluoroacetic anhydride under ice-cooling, and the mixturewas stirred at room temperature overnight. To the reaction mixture wasadded 1 mL of triethylamine, and the mixture was stirred at the sametemperature for 2 hours. To the reaction mixture were added water and 30mL of 1 mol/L hydrochloric acid, and the mixture was extracted threetimes with 30 mL of dichloromethane. The organic layers were combined,washed with water, and brine, and dried over anhydrous magnesiumsulfate. After the solvent was removed under reduced pressure, ethylacetate and hexane were added to the residue, and the crystal wascollected by filtration to give 325 mg ofN-tert-butyl-2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylbenzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm:

1.23 (9H, s), 1.25 (6H, d, J=6.9 Hz), 2.93 (1H, sept, J=6.9 Hz), 3.17(2H, t, J=6.6 Hz), 3.22-3.29 (2H, m), 3.94 (3H, s), 4.36 (1H, br s),5.43 (1H, t, J=5.7 Hz), 6.99 (1H, d, J=8.5 Hz), 7.20 (1H, d, J=7.9 Hz),7.29 (1H, dd, J=7.9, 1.6 Hz), 7.79 (1H, dd, J=8.5, 1.9 Hz), 7.84 (1H, d,J=1.6 Hz), 8.15 (1H, d, J=1.9 Hz)

Reference Example 53Ethyl[2-[2-[(5-cyano-2-methoxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetate

A suspension of 300 mg ofethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate,132 mg of 4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 189 mgof potassium carbonate in 2.0 mL of N,N-dimethylformamide was stirred atroom temperature for 18 hours, then at 50° C. for 3 hours. To thereaction mixture were added 60 mg of4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 45 mg ofpotassium carbonate, and the mixture was stirred at the same temperaturefor 2.7 hours. To the reaction mixture were added 60 mg of4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 45 mg ofpotassium carbonate, and the mixture was stirred at the same temperaturefor 3 hours. Furthermore, to the reaction mixture was added 2 mL ofN,N-dimethylformamide, and the mixture was stirred at the sametemperature for 1.5 hours. To the reaction mixture were added water andsaturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,aqueous sodium chloride solution, and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:ethyl acetate-hexane) to give 311 mg ofethyl[2-[2-[(5-cyano-2-methoxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (CDCl₃) δ ppm:

1.19 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.3 Hz), 2.60 (3H, s), 2.76-2.87(3H, m), 3.57-3.65 (2H, m), 3.92 (3H, s), 4.24 (2H, q, J=7.3 Hz), 4.56(2H, s), 4.67 (2H, s), 6.49 (1H, d, J=1.6 Hz), 6.73 (1H, dd, J=7.6, 1.6Hz), 6.95 (1H, d, J=8.5 Hz), 6.97 (1H, d, J=7.6 Hz), 7.02 (1H, s), 7.71(1H, dd, J=8.5, 2.2 Hz), 8.22 (1H, d, J=2.2 Hz)

Reference Example 54Amino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]-ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate

To a solution of 131 mg ofethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein 5 mL of N,N-dimethylformamide was added 0.91 mL ofN,N-diisopropylethylamine. To the stirred mixture was added 0.069 mL ofbenzyl bromide at 40° C., and the mixture was stirred at roomtemperature over night. To the reaction mixture were added 0.91 mL ofN,N-diisopropylethylamine and 86 mg of 4-nitrophenoxycarbonyloxymethyl2,2-dimethylpropionate, and the mixture was stirred at room temperaturefor 6 hours. To the reaction mixture were added 10 mL of water and 10 mLof brine, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent: ethylacetate-hexane) to give 99 mg ofamino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl 2,2-dimethylpropionate.

¹H-NMR (CDCl₃) δ ppm:

1.19 (6H, d, J=6.9 Hz), 1.22 (9H, s), 1.27 (3H, t, J=7.3 Hz), 2.70-2.86(3H, m), 3.17-3.25 (2H, m), 4.21 (2H, q, J=7.3 Hz), 4.47 (2H, s),5.05-5.11 (1H, m), 5.17 (2H, s), 5.86 (2H, s), 6.50 (1H, d, J=1.6 Hz),6.71 (1H, dd, J=7.6, 1.6 Hz), 6.86 (1H, d, J=7.6 Hz), 7.04 (1H, d, J=8.8Hz), 7.29-7.48 (6H, m), 8.28 (1H, dd, J=8.8, 2.5 Hz), 8.32 (1H, d, J=2.5Hz), 9.40-9.80 (1H, br)

Reference Example 55

The following compounds were prepared according to a similar manner tothat described in Reference Example 54.

Amino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]-ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2-acetoxy-2-methylpropionate

¹H-NMR (CDCl₃) δ ppm:

1.19 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.3 Hz), 1.56 (6H, s), 2.04 (3H,s), 2.73 (2H, t, J=6.9 Hz), 2.81 (1H, sept, J=6.9 Hz), 3.17-3.24 (2H,m), 4.21 (2H, q, J=7.3 Hz), 4.47 (2H, s), 5.09 (1H, t, J=6.0 Hz), 5.16(2H, s), 5.88 (2H, s), 6.50 (1H, d, J=1.6 Hz), 6.70 (1H, dd, J=7.6, 1.6Hz), 6.86 (1H, d, J=7.6 Hz), 6.88-7.17 (1H, m), 7.30-7.48 (5H, m), 8.27(1H, dd, J=8.8, 2.5 Hz), 8.32 (1H, d, J=2.5 Hz), 9.20-9.90 (1H, br)

Ethyl[4-[2-[5-[amino(butoxycarbonylamino)methyl]-2-benzyloxybenzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yl]oxyacetate

¹H-NMR (CDCl₃) δ ppm:

0.95 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz), 1.39-1.50 (2H, m),1.66-1.76 (2H, m), 2.54 (3H, s), 2.85 (2H, t, J=6.9 Hz), 3.21-3.30 (2H,m), 4.12-4.21 (4H, m), 4.58 (2H, s), 5.18 (1H, t, J=6.0 Hz), 5.29 (2H,s), 6.89 (1H, dd, J=7.6, 1.6 Hz), 6.98 (1H, d, J=1.6 Hz), 7.098 (1H, d,J=7.6 Hz), 7.103 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=7.6, 1.3 Hz),7.34-7.43 (3H, m), 7.44-7.50 (2H, m), 7.55 (1H, td, J=7.6, 1.6 Hz), 7.63(1H, td, J=7.6, 1.3 Hz), 8.22 (1H, dd, J=7.6, 1.6 Hz), 8.26 (1H, dd,J=8.8, 2.5 Hz), 8.33 (1H, d, J=2.5 Hz), 9.20-10.00 (1H, br)

Example 1Ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 1)

To a solution of 4.62 g ofethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetatein 40 mL of N,N-dimethylformamide was added 1.03 g of lithium chloride,and the mixture was stirred at 140° C. for 2 hours. After being cooledto room temperature, the reaction mixture was poured into a mixture of60 mL of ethyl acetate, 6 mL of toluene, and 32 mL of 1 mol/Lhydrochloric acid. The organic layer was separated, and washed with 1mol/L hydrochloric acid and brine. The organic layer was dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by columnchromatography on aminopropylated silica gel (eluent: acetic acid-ethylacetate) to give 3.67 g ofethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetateas a colorless amorphous material.

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.3 Hz), 2.71 (3H, s), 2.75-2.82 (2H, m), 3.07-3.16 (2H,m), 4.10 (2H, q, J=7.3 Hz), 4.75 (2H, s), 6.90-6.95 (2H, m), 7.12 (1H,d, J=8.5 Hz), 7.20-7.30 (1H, m), 7.38 (1H, dd, J=7.6, 1.3 Hz), 7.45-7.60(1H, br s), 7.65 (1H, td, J=7.6, 1.3 Hz), 7.75 (1H, td, J=7.6, 1.3 Hz),7.87 (1H, dd, J=8.5, 2.2 Hz), 8.01 (1H, d, J=2.2 Hz), 8.07 (1H, dd,J=7.6, 1.3 Hz), 11.80-12.30 (1H, br)

Example 2Ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate(Compound 2)

To a solution of 148 mg ofethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein 3 mL of N,N-dimethylformamide was added 41 mg of lithium chloride,and the mixture was stirred at 140° C. for 3 hours. After being cooledto room temperature, the reaction mixture was concentrated under reducedpressure. To the residue was added aqueous 10% citric acid solution toadjust pH4, and the mixture was extracted with 100 mL of ethyl acetate.The organic layer was washed with water and brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 139 mg ofethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (6H, d, J=6.9 Hz), 1.18 (3H, t, J=7.3 Hz), 2.60-2.70 (2H, m), 2.78(1H, sept, J=6.9 Hz), 2.95-3.10 (2H, m), 4.14 (2H, q, J=7.3 Hz), 4.73(2H, s), 6.66 (1H, d, J=1.4 Hz), 6.72 (1H, dd, J=7.9, 1.4 Hz), 6.97 (1H,d, J=7.9 Hz), 7.09 (1H, d, J=8.5 Hz), 7.45 (1H, t, J=5.7 Hz), 7.85 (1H,dd, J=8.5, 2.3 Hz), 7.98 (1H, d, J=2.3 Hz), 11.95 (1H, br s)

Example 3

The following compounds were prepared according to a similar manner tothat described in Example 1 or 2.

Ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]3′,4′,5′-trifluorobiphenyl-3-yloxy]acetate(Compound 3)

¹H-NMR (DMSO-d₆) δ ppm:

1.19 (3H, t, J=7.3 Hz), 2.70-2.80 (2H, m), 3.05-3.15 (2H, m), 4.15 (2H,q, J=7.3 Hz), 4.90 (2H, s), 7.06 (1H, d, J=8.5 Hz), 7.15-7.25 (3H, m),7.48 (1H, t, J=5.7 Hz), 7.65-7.75 (2H, m), 7.83 (1H, dd, J=8.5, 2.2 Hz),7.96 (1H, d, J=2.2 Hz), 11.93 (1H, s)

Methyl4′-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-3′-ethoxycarbonylmethoxybiphenyl-2-carboxylate(Compound 4)

¹H-NMR (CDCl₃) δ ppm:

1.32 (3H, t, J=7.3 Hz), 2.94 (2H, t, J=6.0 Hz), 3.30-3.40 (2H, m), 3.79(3H, s), 4.31 (2H, q, J=7.3 Hz), 4.50 (2H, s), 5.84 (1H, t, J=5.0 Hz),6.60 (1H, d, J=1.6 Hz), 6.82 (1H, dd, J=7.6, 1.6 Hz), 6.89 (1H, d, J=8.5Hz), 7.05 (1H, d, J=7.6 Hz), 7.32 (1H, dd, J=7.9, 1.3 Hz), 7.44 (1H, td,J=7.9, 1.3 Hz), 7.55-7.60 (2H, m), 7.91 (1H, dd, J=7.9, 1.3 Hz), 8.06(1H, d, J=2.2 Hz), 8.90-9.10 (1H, br)

Ethyl[2-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetylamino]acetate(Compound 5)

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 1.35 (3H, t, J=6.9 Hz), 2.84-2.92 (3H, m),3.22-3.28 (2H, m), 4.18 (2H, d, J=5.4 Hz), 4.32 (2H, q, J=6.9 Hz), 4.53(2H, s), 5.89-5.94 (1H, m), 6.65 (1H, d, J=1.3 Hz), 6.85 (1H, dd, J=7.9,1.3 Hz), 7.03-7.10 (3H, m), 7.65 (1H, dd, J=8.8, 2.2 Hz), 7.95 (1H, d,J=2.2 Hz), 9.35 (1H, br s)

2-[2-[2-(5-Cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide(Compound 6)

¹H-NMR (DMSO-d₆) δ ppm:

1.16 (6H, d, J=6.9 Hz), 2.68-2.74 (2H, m), 2.77-2.84 (1H, m), 2.98-3.06(2H, m), 4.41 (2H, s), 6.70 (1H, d, J=1.3 Hz), 6.73 (1H, dd, J=7.6, 1.3Hz), 6.98 (1H, d, J=7.6 Hz), 7.11 (1H, d, J=8.8 Hz), 7.24 (1H, br s),7.47-7.54 (2H, m), 7.86 (1H, dd, J=8.8, 2.5 Hz), 7.98 (1H, d, J=2.5 Hz),12.00 (1H, br s)

Ethyl4-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate(Compound 7)

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 1.29 (3H, t, J=7.3 Hz), 2.09-2.17 (2H, m), 2.52(2H, t, J=7.3 Hz), 2.76 (2H, t, J=6.9 Hz), 2.81-2.90 (1H, m), 3.14-3.24(2H, m), 4.00 (2H, t, J=6.0 Hz), 4.19 (2H, q, J=7.3 Hz), 5.53 (1H, t,J=5.7 Hz), 6.66 (1H, d, J=1.3 Hz), 6.74 (1H, dd, J=7.6, 1.3 Hz), 6.94(1H, d, J=7.6 Hz), 7.05 (1H, d, J=8.8 Hz), 7.63 (1H, dd, J=8.8, 1.9 Hz),7.94 (1H, d, J=1.9 Hz), 9.73 (1H, br s)

N-[2-(2-Benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-hydroxybenzenesulfonamide(Compound 8)

¹H-NMR (CDCl₃) δ ppm:

1.24 (6H, d, J=6.9 Hz), 2.78 (2H, t, J=6.3 Hz), 2.83-2.93 (1H, m), 3.24(2H, t, J=6.3 Hz), 5.04 (2H, s), 5.29 (1H, br s), 6.77 (1H, d, J=7.9Hz), 6.80 (1H, s), 6.94 (1H, d, J=7.9 Hz), 7.00 (1H, d, J=8.5 Hz),7.29-7.49 (5H, m), 7.58 (1H, dd, J=8.5, 1.9 Hz), 7.69 (1H, d, J=1.9 Hz)

Ethyl2-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]propionate(Compound 9)

¹H-NMR (CDCl₃) δ ppm:

1.17-1.23 (6H, m), 1.32 (3H, t, J=7.0 Hz), 1.63 (3H, d, J=6.8 Hz),2.59-2.66 (1H, m), 2.79-2.87 (1H, m), 3.05-3.19 (2H, m), 3.47-3.56 (1H,m), 4.25-4.35 (2H, m), 4.91 (1H, q, J=6.8 Hz), 6.31-6.37 (1H, m),6.50-6.53 (1H, m), 6.71-6.75 (1H, m), 6.91 (1H, d, J=7.6 Hz), 6.99 (1H,d, J=8.7 Hz), 7.59 (1H, dd, J=8.7, 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 9.39(1H, br s)

2-[2-[2-(5-Cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-N,N-dimethylacetamide(Compound 10)

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 2.61-2.70 (2H, m), 2.72-2.84 (1H, m), 2.84 (3H,s), 2.99 (3H, s), 3.00-3.10 (2H, m), 4.74 (2H, s), 6.66-6.75 (2H, m),6.95 (1H, d, J=7.9 Hz), 7.12 (1H, d, J=8.3 Hz), 7.42-7.51 (1H, m), 7.85(1H, dd, J=8.3, 2.2 Hz), 7.97 (1H, d, J=2.2 Hz), 12.00 (1H, br s)

5-Cyano-2-hydroxy-N-[2-[4-isopropyl-2-(2-morpholin-4-yl-2-oxoethoxy)-phenyl]ethyl]benzenesulfonamide(Compound 11)

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 2.61-2.69 (2H, m), 2.74-2.83 (1H, m), 2.99-3.10(2H, m), 3.42-3.52 (4H, m), 3.53-3.63 (4H, m), 4.76 (2H, s), 6.68-6.75(2H, m), 6.96 (1H, d, J=7.6 Hz), 7.10 (1H, d, J=8.2 Hz), 7.47 (1H, t,J=5.7 Hz), 7.85 (1H, dd, J=8.2, 1.9 Hz), 7.98 (1H, d, J=1.9 Hz), 11.95(1H, br s)

Ethyl[2′-tert-butylsulfamoyl-4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]biphenyl-3-yloxy]acetate(Compound 12)

¹H-NMR (DMSO-d₆) δ ppm:

0.92 (9H, s), 1.16 (3H, t, J=6.9 Hz), 2.70-2.80 (2H, m), 3.00-3.15 (2H,m), 4.12 (2H, q, J=6.9 Hz), 4.71 (2H, s), 6.89 (1H, dd, J=7.6, 1.6 Hz),6.95 (1H, d, J=1.6 Hz), 7.00-7.10 (1H, br s), 7.10-7.50 (4H, m), 7.54(1H, td, J=7.6, 1.3 Hz), 7.62 (1H, td, J=7.6, 1.3 Hz), 7.78 (1H, br s),7.94 (1H, br s), 8.03 (1H, dd, J=7.6, 1.3 Hz), 11.50-12.50 (1H, br)

Ethyl[2-[2-[(5-cyano-2-hydroxybenzenesulfonyl)-(2-methyl-[3-thiazole-4-ylmethyl)amino)ethyl]-5-isopropylphenoxy]acetate(Compound 13)

¹H-NMR (DMSO-d₆) δ ppm:

1.08-1.20 (9H, m), 2.56-2.65 (5H, m), 2.68-2.83 (1H, m), 3.16-3.36 (2H,m), 4.12 (2H, q, J=7.3 Hz), 4.62 (2H, s), 4.68 (2H, s), 6.12 (1H, d,J=8.8 Hz), 6.55-6.65 (2H, m), 6.66-6.72 (1H, m), 6.83-6.89 (1H, m), 7.09(1H, dd, J=8.8, 2.5 Hz), 7.19 (1H, s), 7.58-7.63 (1H, m)

N-tert-Butyl-2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylbenzenesulfonamide(Compound 14)

¹H-NMR (CDCl₃) δ ppm:

1.20-1.31 (15H, m), 2.93-3.01 (1H, m), 3.14-3.24 (2H, m), 3.30-3.41 (2H,m), 4.41-4.55 (1H, m), 5.55-6.30 (1H, br), 6.97-7.09 (1H, m), 7.11-7.21(1H, m), 7.56-7.66 (1H, m), 7.81-7.90 (1H, m), 7.97-8.11 (1H, m)

Example 4

The following compound was prepared according to the similar manner tothat described in Reference Example 37 and Example 1 or 2.

Ethyl3-[2-[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]propionate(Compound 15)

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.3 Hz), 2.80 (2H, t, J=7.3 Hz), 3.07-3.14 (2H, m),3.35-3.45 (2H, m), 4.01 (2H, q, J=7.3 Hz), 4.60 (2H, s), 7.07 (1H, d,J=8.5 Hz), 7.15-7.25 (3H, m), 7.47-7.54 (1H, m), 7.65-7.75 (2H, m), 7.83(1H, dd, J=8.5, 2.2 Hz), 7.87 (1H, t, J=6.0 Hz), 7.96 (1H, d, J=2.2 Hz),11.96 (1H, br s)

Example 55-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide(Compound 16)

Ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate(0.266 g) was dissolved in 5 mL of ethanol. To the solution was added0.087 mL of hydrazine monohydrate at room temperature, and the mixturewas refluxed for 1 hour. The solvent was removed under reduced pressureto give 0.258 g of5-cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide.

¹H-NMR (DMSO-d₆) δ ppm:

1.17 (6H, d, J=6.9 Hz), 2.66-2.73 (2H, m), 2.75-2.84 (3H, m), 4.47 (2H,s), 5.42 (1H, br s), 6.30 (1H, d, J=8.8 Hz), 6.73-6.77 (2H, m), 7.01(1H, d, J=7.9 Hz), 7.22 (1H, dd, J=8.8, 2.5 Hz), 7.56 (1H, d, J=2.5 Hz),9.00-9.60 (1H, m)

Example 65-Cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide(Compound 17)

5-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)-ethyl]-2-hydroxybenzenesulfonamide(0.258 g) was dissolved in 10 mL of tetrahydrofuran. To the stirredsolution was added 0.177 g of triphosgene under ice-cooling, and themixture was stirred at room temperature for 30 minutes. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 0.26 g of5-cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-methoxy)phenyl]ethyl]benzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm:

1.23 (6H, d, J=6.9 Hz), 2.74-2.91 (3H, m), 3.18-3.24 (2H, m), 4.96 (2H,s), 5.50-5.55 (1H, m), 6.70-6.71 (1H, m), 6.81-6.85 (1H, m), 6.99 (1H,d, J=8.5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.64 (1H, dd, J=8.8, 1.9 Hz), 7.92(1H, d, J=1.9 Hz), 9.17-9.57 (2H, m)

Example 75-Cyano-2-hydroxy-N-[2-(2-hydroxy-4-isopropylphenyl)-ethyl]benzenesulfonamide(Compound 18)

To a stirred solution of 0.203 g ofN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-hydroxybenzenesulfonamidein ethanol was added 0.04 g of 10% palladium on carbon, and the mixturewas stirred under a hydrogen atmosphere and ordinary pressure for 3hours. After the insoluble material was removed by filtration, thefiltrate was concentrated under reduced pressure to give 0.143 g of5-cyano-2-hydroxy-N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]benzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm:

1.21 (6H, d, J=7.3 Hz), 2.71-2.86 (3H, m), 3.22-3.32 (2H, m), 6.59 (1H,s), 6.72 (1H, d, J=7.6 Hz), 6.89 (1H, d, J=7.6 Hz), 7.02 (1H, d, J=8.5Hz), 7.59-7.64 (1H, m), 7.85-7.89 (1H, m)

Example 8Ethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 19)

A suspension of 149 mg ofethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetatein 1.0 mL of saturated hydrogen chloride ethanol solution was stirred atroom temperature for 3 hours, and the reaction mixture was concentratedunder reduced pressure. To a solution of the residue in 1.0 mL ofethanol was added 206 mg of ammonium acetate, and the mixture wasstirred at room temperature for 13 hours. The reaction mixture wasconcentrated under reduced pressure to give white solid, which wastriturated successively with water, and ethyl acetate-ethanol to give141 mg ofethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateas a white powder.

¹H-NMR (DMSO-d₆) δ ppm:

1.13 (3H, t, J=7.3 Hz), 2.72 (3H, s), 2.75-2.85 (2H, m), 2.90-3.00 (2H,m), 4.09 (2H, q, J=7.3 Hz), 4.76 (2H, s), 6.43 (1H, d, J=8.9 Hz),6.90-6.95 (2H, m), 7.20 (1H, d, J=7.9 Hz), 7.39 (1H, dd, J=7.6, 1.3 Hz),7.57 (1H, dd, J=8.9, 2.3 Hz), 7.65 (1H, td, J=7.6, 1.3 Hz), 7.74 (1H,td, J=7.6, 1.3 Hz), 7.85-8.15 (4H, m), 8.45-8.80 (2H, br)

Example 9Ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate(Compound 20)

A solution of 16.09 g ofethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein 200 mL of 37% hydrogen chloride ethanol solution was stirred at roomtemperature for 4 hours, and the reaction mixture was concentrated underreduced pressure. To a stirred solution of the residue in 180 ml ofethanol was added 27.78 g of ammonium acetate under ice-cooling, and themixture was stirred at room temperature for 18 hours. The reactionmixture was concentrated under reduced pressure, and 10 mL of ethylacetate, 200 mL of water, and 40 mL of hexane were added successively tothe residue. The precipitates were collected by filtration, and washedsuccessively with 1000 mL of water and a mixture of 80 mL of hexane and20 mL of ethyl acetate to give 15.11 g ofethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 1.17 (3H, t, J=7.3 Hz), 2.65-2.75 (2H, m),2.75-2.90 (3H, m), 4.13 (2H, q, J=7.3 Hz), 4.75 (2H, s), 6.27 (1H, d,J=9.1 Hz), 6.67 (1H, d, J=1.1 Hz), 6.70-6.85 (2H, m), 7.00 (1H, d, J=7.3Hz), 7.50 (1H, dd, J=9.1, 2.6 Hz), 7.85 (2H, br s), 7.95 (1H, d, J=2.6Hz), 8.47 (1H, br s)

Example 10

The following compounds were prepared according to a similar manner tothat described in Example 8 or 9.

Ethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetate(Compound 21)

¹H-NMR (DMSO-d₆) δ ppm:

1.18 (3H, t, J=7.3 Hz), 2.77 (2H, t, J=6.9 Hz), 2.87 (2H, t, J=6.9 Hz),4.13 (2H, q, J=7.3 Hz), 4.93 (2H, s), 6.26 (1H, d, J=9.1 Hz), 6.80-6.90(1H, br s), 7.20-7.30 (3H, m), 7.50 (1H, dd, J=9.1, 2.8 Hz), 7.65-7.75(2H, m), 7.90-8.35 (4H, m)

Ethyl3-[2-[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]propionate(Compound 22)

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.3 Hz), 2.75-2.95 (4H, m), 3.44 (2H, q, J=6.0 Hz), 4.02(2H, q, J=7.3 Hz), 4.62 (2H, s), 6.29 (1H, d, J=9.1 Hz), 6.86 (1H, brs), 7.15-7.30 (3H, m), 7.51 (1H, dd, J=9.1, 2.8 Hz), 7.65-7.75 (2H, m),7.86 (1.5H, br s), 7.96 (1H, d, J=2.8 Hz), 8.12 (1H, t, J=6.0 Hz), 8.51(1.5H, br s)

Methyl4′-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′-ethoxycarbonylmethoxybiphenyl-2-carboxylate(Compound 23)

¹H-NMR (DMSO-d₆) δ ppm:

1.17 (3H, t, J=6.9 Hz), 2.77 (2H, t, J=7.3 Hz), 2.89 (2H, t, J=7.3 Hz),3.58 (3H, s), 4.14 (2H, q, J=6.9 Hz), 4.32-4.38 (1H, br), 4.78 (2H, s),6.30 (1H, d, J=9.5 Hz), 6.73 (1H, d, J=1.6 Hz), 6.80 (1H, dd, J=7.9, 1.6Hz), 7.16 (1H, d, J=7.9 Hz), 7.35-7.55 (3H, m), 7.59 (1H, td, J=7.9, 1.3Hz), 7.68 (1H, dd, J=7.9, 1.3 Hz), 7.85 (1.5H, br s), 7.97 (1H, d, J=2.8Hz), 8.50 (1.5H, br s)

Ethyl[2-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetylamino]acetate(Compound 24)

¹H-NMR (DMSO-d₆) δ ppm:

1.17 (6H, d, J=7.3 Hz), 1.20 (3H, t, J=7.3 Hz), 2.70-2.75 (2H, m),2.78-2.85 (3H, m), 3.97 (2H, d, J=5.4 Hz), 4.11 (2H, q, J=7.3 Hz), 4.52(2H, s), 6.27 (1H, d, J=9.1 Hz), 6.75-6.81 (3H, m), 7.04 (1H, d, J=8.2Hz), 7.50 (1H, dd, J=9.1, 2.5 Hz), 7.86 (2H, br s), 7.94 (1H, d, J=2.5Hz), 8.43-8.53 (3H, m)

Acetic acid salt of2-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetamide(Compound 25)

¹H-NMR (DMSO-d₆) δ ppm:

1.16 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.68-2.74 (2H, m), 2.77-2.84 (3H,m), 4.39 (2H, s), 6.30 (1H, d, J=9.5 Hz), 6.71 (1H, d, J=1.3 Hz), 6.76(1H, dd, J=7.6, 1.3 Hz), 7.02 (1H, d, J=7.6 Hz), 7.42-7.48 (3H, m), 7.50(1H, dd, J=9.5, 2.5 Hz), 7.94 (1H, d, J=2.5 Hz), 7.95-8.68 (4H, m)

4-Hydroxy-3-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethylsulfamoyl]benzamidinehydrochloride (Compound 26)

¹H-NMR (DMSO-d₆) δ ppm:

1.16 (6H, d, J=6.9 Hz), 2.61-2.67 (2H, m), 2.77-2.86 (1H, m), 2.92-3.02(2H, m), 5.01 (2H, s), 6.77 (1H, dd, J=7.9, 1.3 Hz), 6.92 (1H, d, J=1.13Hz), 6.99 (1H, d, J=7.9 Hz), 7.20 (1H, d, J=8.5 Hz), 7.39 (1H, t, J=6.0Hz), 7.88 (1H, dd, J=8.5, 2.5 Hz), 8.14 (1H, d, J=2.5 Hz), 8.87 (2H, brs), 9.24 (2H, br s), 12.01 (1H, br s), 12.51 (1H, br s)

Ethyl4-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]butyratehydrochloride (Compound 27)

¹H-NMR (DMSO-d₆) δ ppm:

1.16 (6H, d, J=6.6 Hz), 1.17 (3H, t, J=7.3 Hz), 1.87-1.95 (2H, m), 2.45(2H, t, J=7.3 Hz), 2.60-2.66 (2H, m), 2.75-2.85 (1H, m), 2.92-3.00 (2H,m), 3.92 (2H, t, J=6.3 Hz), 4.06 (2H, q, J=7.3 Hz), 6.66-6.71 (1H, m),6.72-6.76 (1H, m), 6.94 (1H, d, J=7.9 Hz), 7.19 (1H, d, J=8.8 Hz), 7.37(1H, t, J=5.7 Hz), 7.87 (1H, dd, J=8.8, 2.5 Hz), 8.15 (1H, d, J=2.5 Hz),8.86 (2H, br s), 9.25 (2H, br s), 12.01 (1H, br s)

4-Hydroxy-3-[2-(2-hydroxy-4-isopropylphenyl)ethylsulfamoyl]benzamidine(Compound 28)

¹H-NMR (DMSO-d₆) δ ppm:

1.13 (6H, d, J=6.9 Hz), 2.56-2.62 (2H, m), 2.66-2.81 (3H, m), 6.27 (1H,d, J=9.1 Hz), 6.56 (1H, dd, J=7.6, 1.6 Hz), 6.61 (1H, d, J=1.6 Hz), 6.89(1H, d, J=7.6 Hz), 7.49 (1H, dd, J=9.1, 2.8 Hz), 7.79 (2H, br s), 7.93(1H, d, J=2.8 Hz), 8.46 (2H, br s)

Ethyl2-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]propionate(Compound 29)

¹H-NMR (DMSO-d₆) δ ppm:

1.09-1.14 (9H, m), 1.45 (3H, d, J=6.6 Hz), 2.61-2.88 (5H, m), 4.09 (2H,q, J=6.9 Hz), 4.88 (1H, q, J=6.6 Hz), 6.27 (1H, d, J=9.1 Hz), 6.58 (1H,d, J=1.6 Hz), 6.72 (1H, dd, J=7.9, 1.6 Hz), 7.00 (1H, d, J=7.9 Hz), 7.42(1H, d, J=9.1, 2.8 Hz), 7.93 (1H, d, J=2.8 Hz)

2-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]-N,N-dimethylacetamide(Compound 30)

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 2.62-2.70 (2H, m), 2.73-2.85 (6H, m), 2.98 (3H,s), 4.73 (2H, s), 6.26 (1H, d, J=9.5 Hz), 6.70-6.74 (2H, m), 6.85 (1H,brs), 6.99 (1H, d, J=8.4 Hz), 7.49 (1H, dd, J=9.5, 3.2 Hz), 7.92 (1H, d,J=3.2 Hz), 8.32 (2H, br s), 8.94 (2H, br s)

4-Hydroxy-3-[2-[4-isopropyl-2-(2-morpholin-4-yl-2-oxoethoxy)phenyl]-ethylsulfamoyl]benzamidine(Compound 31)

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 2.60-2.70 (2H, m), 2.73-2.88 (3H, m), 3.39-3.59(8H, m), 4.31-4.36 (1H, m), 4.76 (2H, s), 6.26 (1H, d, J=9.5 Hz),6.69-6.76 (2H, m), 6.82 (1H, br s), 7.00 (1H, d, J=8.2 Hz), 7.49 (1H,dd, J=9.5, 2.5 Hz), 7.68-8.62 (4H, m)

Acetic acid salt ofethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-sulfamoylbiphenyl-3-yloxy]acetate(Compound 32)

¹H-NMR (DMSO-d₆) δ ppm:

1.12 (3H, t, J=7.3 Hz), 1.90 (3H, s), 2.80 (2H, t, J=6.3 Hz), 2.90-3.00(2H, m), 4.01 (2H, q, J=7.3 Hz), 4.53 (2H, s), 6.42 (1H, d, J=9.1 Hz),6.91 (1H, dd, J=7.6, 1.6 Hz), 6.98 (1H, d, J=1.6 Hz), 7.15 (1H, d, J=7.6Hz), 7.30 (1H, dd, J=7.6, 1.3 Hz), 7.50-7.57 (2H, m), 7.61 (1H, td,J=7.6, 1.3 Hz), 7.69 (2H, br s), 7.96 (1H, d, J=2.8 Hz), 8.06 (1H, dd,J=7.6, 1.3 Hz), 8.10-8.25 (1.5H, br), 8.40-8.60 (1.5H, br)

Example 11[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]aceticacidhydrochloride (Compound 33)

To a solution of 290 mg ofethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]acetatein 1.0 mL of acetonitrile was added 0.756 mL of 2 mol/L sodium hydroxidesolution, and the mixture was stirred at room temperature for 30minutes. To the reaction mixture was added 1.26 mL of 2 mol/Lhydrochloric acid, and the mixture was concentrated under reducedpressure. To the residue was added water, and the mixture was purifiedby column chromatography on trimethylaminopropylated silica gel (eluent:10% 1 mol/L hydrochloric acid-acetonitrile). The eluent was concentratedunder reduced pressure to give 260 mg of[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]aceticacid hydrochloride as a white solid.

¹H-NMR (DMSO-d₆) δ ppm:

2.73 (3H, s), 2.80 (2H, t, J=7.3 Hz), 3.10 (2H, t, J=7.3 Hz), 4.65 (2H,s), 6.85-6.95 (2H, m), 7.16 (1H, d, J=7.6 Hz), 7.23 (1H, d, J=8.3 Hz),7.37 (1H, dd, J=7.3, 1.3 Hz), 7.66 (1H, td, J=7.6, 1.3 Hz), 7.75 (1H,td, J=7.6, 1.3 Hz), 7.89 (1H, dd, J=8.3, 2.1 Hz) 8.08 (1H, dd, J=7.9,1.3 Hz), 8.17 (1H, d, J=2.1 Hz), 8.91 (2H, br s), 9.28 (2H, br s)

Example 12

The following compounds were prepared according to a similar manner tothat described in Example 11.

[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]aceticacid hydrochloride (Compound 34)

¹H-NMR (DMSO-d₆) δ ppm:

2.76 (2H, t, J=7.3 Hz), 3.00-3.15 (2H, m), 4.82 (2H, s), 7.10-7.25 (4H,m), 7.35-7.45 (1H, br s), 7.65-7.75 (2H, m), 7.87 (1H, dd, J=8.6, 2.1Hz), 8.14 (1H, d, J=2.1 Hz), 8.89 (2H, br s), 9.27 (2H, br s),11.70-12.40 (1H, br), 12.60-13.30 (1H, br)

3-[2-[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]-propionicacid (Compound 35)

¹H-NMR (DMSO-d₆) δ ppm:

2.45 (2H, t, J=6.0 Hz), 2.75-2.90 (4H, m), 3.41 (2H, q, J=6.0 Hz), 4.56(2H, s), 6.55 (1H, d, J=8.8 Hz), 7.20-7.30 (3H, m), 7.61 (1H, dd, J=8.8,2.8 Hz), 7.70-7.80 (2H, m), 7.89 (1H, t, J=6.0 Hz), 8.00 (1H, d, J=2.8Hz), 8.17 (1.5H, br s), 8.77 (1.5H, br s)

Methyl4′-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′-carboxymethoxybiphenyl-2-carboxylatehydrochloride (Compound 36)

¹H-NMR (DMSO-d₆) δ ppm:

2.77 (2H, t, J=7.3 Hz), 3.08 (2H, t, J=7.3 Hz), 3.59 (3H, s), 4.64 (2H,s), 6.71 (1H, d, J=1.6 Hz), 6.78 (1H, dd, J=7.6, 1.6 Hz), 7.10-7.20 (2H,m), 7.40 (1H, d, J=7.3 Hz), 7.47 (1H, d, J=7.6, 1.3 Hz), 7.60 (1H, td,J=7.3, 1.3 Hz), 7.68 (1H, dd, J=7.6, 1.3 Hz), 7.86 (1H, dd, J=8.5, 2.2Hz), 8.15 (1H, d, J=2.2 Hz), 8.82 (2H, br s), 9.25 (2H, br s)

[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]aceticacid hydrochloride (Compound 37)

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (6H, d, J=6.9 Hz), 2.68 (2H, t, J=7.6 Hz), 2.78 (1H, sept, J=6.9Hz), 2.95-3.05 (2H, m), 4.64 (2H, s), 6.65-6.70 (1H, m), 6.72 (1H, dd,J=7.8, 1.2 Hz), 6.97 (1H, d, J=7.8 Hz), 7.25 (1H, d, J=8.4 Hz),7.30-7.45 (1H, m), 7.90 (1H, dd, J=8.4, 2.8 Hz), 8.15 (1H, dd, J=2.8Hz), 8.99 (2H, br s), 9.29 (2H, s), 12.13 (1H, br s), 12.94 (1H, br s)

[2-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetylamino]aceticacid (Compound 38)

¹H-NMR (DMSO-d₆) δ ppm:

1.16 (6H, d, J=6.9 Hz), 2.72-2.77 (2H, m), 2.78-2.86 (3H, m), 3.79 (2H,d, J=5.7 Hz), 4.47 (2H, s), 6.54 (1H, d, J=9.1 Hz), 6.76 (1H, dd, J=7.6,1.3 Hz), 6.78-6.79 (1H, m), 7.03 (1H, d, J=7.6 Hz), 7.59 (1H, dd, J=9.1,2.5 Hz), 7.99 (1H, d, J=2.5 Hz), 8.09-8.21 (3H, m), 8.70-8.86 (2H, m)

4-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]butyricacid (Compound 39)

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=7.3 Hz), 1.85-1.98 (2H, m), 2.42 (2H, t, J=7.3 Hz),2.59-2.69 (2H, m), 2.72-2.86 (3H, m), 3.90 (2H, t, J=6.0 Hz), 6.68 (1H,d, J=7.6 Hz), 6.72 (1H, s), 6.80 (1H, d, J=8.5 Hz), 6.97 (1H, d, J=7.6Hz), 7.66-7.77 (1H, m), 8.00-8.11 (1H, m), 8.49 (2H, br s), 8.93 (2H, brs)

2-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]propionicacid hydrochloride (Compound 40)

¹H-NMR (DMSO-d₆) δ ppm:

1.09-1.16 (6H, m), 1.43 (3H, d, J=6.6 Hz), 2.56-2.81 (3H, m), 2.91-3.08(2H, m), 4.77 (1H, q, J=6.6 Hz), 6.59 (1H, s), 6.70 (1H, d, J=7.9 Hz),6.96 (1H, d, J=7.9 Hz), 7.23 (1H, d, J=8.8 Hz), 7.35 (1H, br s), 7.89(1H, d, J=8.8, 2.5 Hz), 8.15 (1H, d, J=2.5 Hz), 8.96 (2H, br s), 9.28(2H, br s), 12.12 (1H, br s), 12.95 (1H, br s)

[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-sulfamoylbiphenyl-3-yloxy]aceticacid hydrochloride (Compound 41)

¹H-NMR (DMSO-d₆) δ ppm:

2.75-2.85 (2H, m), 3.05-3.15 (2H, m), 4.63 (2H, s), 6.87 (1H, d, J=1.6Hz), 6.91 (1H, dd, J=7.6, 1.6 Hz), 7.05-7.12 (3H, m), 7.20 (1H, d, J=8.5Hz), 7.29 (1H, dd, J=7.6, 1.3 Hz), 7.40-7.50 (1H, br s), 7.55 (1H, td,J=7.6, 1.3 Hz), 7.61 (1H, td, J=7.6, 1.3 Hz), 7.88 (1H, dd, J=8.5, 2.5Hz), 8.02 (1H, dd, J=7.6, 1.3 Hz), 8.17 (1H, d, J=2.5 Hz), 8.83 (2H, brs), 9.26 (2H, br s), 12.00 (1H, br s), 12.90 (1H, br s)

Example 13[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]aceticacid (Compound 42)

Ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate(50 mg) was dissolved in a mixture of 3 mL of 1 mol/L hydrochloric acidand 1 mL of acetonitrile at 60° C. The solution was stirred at 60° C.for 4 hours, and the colorless solid obtained by concentration underreduced pressure of the reaction mixture was dissolved in a mixture of 3mL of 1 mol/L hydrochloric acid and 1 mL of acetonitrile at 60° C. Afterthe solution was stirred at 60° C. for 4 hours, then at room temperaturefor 10 hours, the reaction mixture was concentrated under reducedpressure to give a colorless solid. The solid was triturated with waterand diethyl ether, and collected by filtration to give 31 mg of[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 2.61-2.83 (3H, m), 3.05 (2H, t, J=7.6 Hz), 4.42(2H, s), 6.67 (1H, s), 6.69 (1H, d, J=7.5 Hz), 6.82 (1H, d, J=9.1 Hz),6.98 (1H, d, J=7.5 Hz), 7.69 (1H, dd, J=9.1, 2.5 Hz), 8.05 (1H, d, J=2.5Hz), 8.56 (2H, br s), 8.94 (2H, br s)

Example 14Ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 43)

A suspension of 2.01 g ofethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl-2′-methanesulfonylbiphenyl-3-yloxy]-acetatein 1.0 mL of saturated hydrogen chloride ethanol solution was stirred atroom temperature for 3 hours. The reaction mixture was concentratedunder reduced pressure, and the residue was dissolved in 20.0 mL ofethanol. To this solution was added 3.34 g of hydroxylammonium acetate,and the mixture was stirred at room temperature for 13 hours. Thereaction mixture was poured into ethyl acetate-water, and the organiclayer was separated. After the aqueous layer was extracted with ethylacetate, and the organic layers were combined, and washed with brine.The organic layer was dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:ethyl acetate) to give 1.90 g ofethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateas an amorphous material.

¹H-NMR (DMSO-d₆) δ ppm:

1.12 (3H, t, J=6.9 Hz), 2.70 (3H, s), 2.75-2.85 (2, m), 3.00-3.10 (2H,m), 4.08 (2H, q, J=6.9 Hz), 4.75 (2H, s), 5.77 (2H, br s), 6.85-6.95(2H, m), 6.97 (1H, d, J=8.5 Hz), 7.10-7.25 (2H, m), 7.35-7.40 (1H, m)7.60-7.80 (3H, m), 7.95-8.10 (2H, m), 9.53 (1H, br s), 10.9 (1H, br s)

Example 15

The following compound was prepared according to a similar manner tothat described in Example 14.

Ethyl[2-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]-ethyl]-5-isopropylphenoxy]acetate(Compound 44)

¹H-NMR (DMSO-d₆) δ ppm:

1.13 (6H, d, J=6.9 Hz), 1.16 (3H, t, J=7.3 Hz), 2.65-2.71 (2H, m),2.73-2.84 (1H, m), 2.93-3.00 (2H, m), 4.12 (2H, q, J=7.3 Hz), 4.73 (2H,s), 5.77 (2H, br s), 6.65 (1H, d, J=1.3 Hz), 6.72 (1H, dd, J=7.9, 1.3Hz), 6.95 (1H, d, J=8.5 Hz), 6.96 (1H, d, J=7.9 Hz), 7.08 (1H, br s),7.69 (1H, dd, J=8.5, 2.2 Hz), 7.99 (1H, d, J=2.2 Hz), 9.53 (1H, br s),10.85 (1H, br s)

Example 16[4-[2-(5-Cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid (Compound 45)

To a stirred solution of 154 g ofethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetatein 1.23 L of ethanol was added 275 mL of 2 mol/L sodium hydroxidesolution under ice-cooling, and the mixture was stirred underice-cooling for 1.5 hours. To the reaction mixture was added dropwise275 mL of 2 mol/L hydrochloric acid, and ethanol was removed underreduced pressure. The residue was extracted with ethyl acetate, and theorganic layer was washed with brine. The solvent was dried overanhydrous magnesium sulfate, and removed under reduced pressure to give149 g of[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm:

2.73 (3H, s), 2.75-2.85 (2H, m), 3.05-3.20 (2H, m), 4.66 (2H, s),6.85-6.95 (2H, m), 7.13 (1H, d, J=8.5 Hz), 7.17 (1H, d, J=7.6 Hz), 7.39(1H, dd, J=7.5, 1.3 Hz), 7.50-7.60 (1H, m), 7.60-7.70 (1H, m), 7.88 (1H,dd, J=8.5, 2.1 Hz), 8.02 (1H, d, J=2.1 Hz), 8.08 (1H, dd, J=8.0, 1.3Hz), 11.80-12.20 (1H, br), 12.70-13.30 (1H, br)

Example 17 Sodium[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 46)

To a stirred solution of 146 g of[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-aceticacid in 580 mL of ethanol was added 137 mL of 2 mol/L sodium hydroxidesolution under ice-cooling, and the solvent was removed under reducedpressure. The residue was suspended with 1.16 L of ethanol, and themixture was stirred under reflux for an hour, then at room temperatureovernight. The obtained white solid was collected by filtration to give129 g of sodium[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm:

2.71 (3H, s), 2.75-2.85 (2H, m), 3.10-3.25 (2H, m), 4.39 (2H, s), 6.73(1H, d, J=8.5 Hz), 6.80-6.90 (2H, m), 7.17 (1H, d, J=8.2 Hz), 7.40 (1H,dd, J=7.6, 1.3 Hz), 7.49 (1H, dd, J=8.8, 2.2 Hz), 7.60-7.70 (1H, m),7.70-7.80 (2H, m), 8.08 (1H, dd, J=8.2, 1.3 Hz)

Example 18[4-[2-[2-Hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid (Compound 47)

Method 1) To a suspension of 79 mg ofethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein acetonitrile was added 0.401 mL of 1 mol/L sodium hydroxide solution,and the mixture was stirred at room temperature for 30 minutes. To thereaction mixture was added 0.401 mL of 1 mol/L hydrochloric acid, andthe mixture was concentrated under reduced pressure. To the residue wasadded water, and the mixture was purified by column chromatography ontrimethylaminopropylated silica gel (eluent: 10% 1 mol/L hydrochloricacid-acetonitrile). The eluent was concentrated under reduced pressure,and the residue was triturated with ethyl acetate to collect byfiltration of 70 mg of[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid as a yellow powder.

Method 2) To a stirred solution of 117 g of sodium[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetatein 1.17 L of water was added 56 g of 50% aqueous hydroxylamine solutionat room temperature, and the mixture was stirred at 70° C. for 4 hours.To the reaction mixture was added dropwise 1 mol/L hydrochloric acid atroom temperature, and the mixture was stirred at the same temperatureover night. The obtained solid was collected by filtration to give 110 gof[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonyl-amino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm:

2.73 (3H, s), 2.75-2.85 (2H, m), 3.05-3.15 (2H, m), 4.67 (2H, s),6.85-6.95 (2H, m), 7.16 (1H, d, J=7.9 Hz), 7.24 (1H, d, J=8.5 Hz),7.35-7.50 (2H, m), 7.66 (1H, td, J=7.6, 1.3 Hz), 7.70-7.85 (2H, m),8.00-8.10 (2H, m), 8.45-9.60 (1H, br), 10.80-13.30 (3H, br)

Example 19 n-Butyl[4-[2-[2-Hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatehydrochloride (Compound 48)

Method 1) A solution of 1.499 g ofethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein 20 mL of 34% hydrogen chloride n-butanol solution was stirred at 60°C. for 3 hours. After being concentrated under reduced pressure, thereaction mixture was recrystallized from n-butanol-diisopropyl ether togive 1.472 g of n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatehydrochloride as a white crystal.

Method 2) A solution of 110 g of[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid in 1.00 L of 14% hydrogen chloride n-butanol solution was stirredat 100° C. for 2.5 hours. The reaction mixture was concentrated underreduced pressure, and the residue was washed with ethyl acetate to give111 g of crude crystal. The crude crystal was recrystallized fromn-butanol-diisopropyl ether to give 83.3 g of n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatehydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

0.78 (3H, t, J=7.6 Hz), 1.15-1.30 (2H, m), 1.40-1.55 (2H, m), 2.72 (3H,s), 2.75-2.85 (2H, m), 3.05-3.15 (2H, m), 4.05 (2H, t, J=6.6 Hz), 4.78(2H, s), 6.90-6.95 (2H, m), 7.18 (1H, d, J=7.6 Hz), 7.20-7.30 (1H, m),7.37 (1H, d, J=7.6 Hz), 7.42-7.50 (1H, m), 7.66 (1H, td, J=7.6, 1.3 Hz),7.72-7.82 (2H, m), 8.02-8.10 (2H, m), 8.60-9.60 (1H, br), 10.85-11.30(1H, br), 11.80-12.20 (1H, br), 12.50-13.05 (1H, br)

Example 20

The following compounds were prepared according to a similar manner tothat described in Example 19.

Cyclohexyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 49)

¹H-NMR (CDCl₃) δ ppm:

1.10-1.60 (6H, m), 1.64-1.74 (2H, m), 1.78-1.88 (2H, m), 2.66 (3H, s),2.93 (2H, t, J=6.0 Hz), 3.35 (2H, t, J=6.0 Hz), 4.62 (2H, s), 4.82-4.90(1H, m), 4.95 (2H, s), 5.90-6.05 (1H, br s), 6.85-7.00 (3H, m), 7.12(1H, d, J=7.6 Hz), 7.36 (1H, dd, J=7.9, 1.3 Hz), 7.57 (1H, td, J=7.9,1.3 Hz), 7.62-7.73 (2H, m), 7.96 (1H, d, J=2.2 Hz), 8.21 (1H, dd, J=7.9,1.3 Hz)

Isopropyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 50)

¹H-NMR (CDCl₃) δ ppm:

1.26 (6H, d, J=6.3 Hz), 2.65 (3H, s), 2.93 (2H, t, J=6.0 Hz), 3.30-3.40(2H, m), 4.61 (2H, s), 4.99 (2H, br s), 5.05-5.15 (1H, m), 6.04 (1H, brs), 6.85-7.05 (3H, m), 7.12 (1H, d, J=7.6 Hz), 7.34-7.45 (1H, m),7.50-7.80 (3H, m), 7.95-8.00 (1H, m), 8.15-8.30 (1H, m)

Example 21Ethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetate(Compound 51)

A solution of 174 mg ofethyl[2-[2-[(5-cyano-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetatein hydrogen chloride ethanol solution was stirred at room temperaturefor 5 hours. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in 3 mL of ethanol. To thestirred mixture was added 135 mg of ammonium acetate under ice-cooling,and the mixture was stirred at room temperature for 2 days. To thereaction mixture was added water, and the precipitate was collected byfiltration, and washed with water to give 71 mg ofethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm:

1.08-1.19 (9H, m), 2.56-2.67 (5H, m), 2.70-2.81 (1H, m), 3.25-3.33 (2H,m), 4.11 (2H, q, J=7.3 Hz), 4.63 (2H, s), 4.67 (2H, s), 6.22 (1H, d,J=9.1 Hz), 6.62 (1H, s), 6.66-6.72 (1H, m), 6.88 (1H, d, J=7.6 Hz), 7.20(1H, s), 7.45 (1H, dd, J=9.1, 2.8 Hz), 7.54-7.96 (2H, br), 8.06 (1H, d,J=2.8 Hz), 8.14-8.67 (2H, br)

Example 22

The following compound was prepared according to a similar manner tothat described in Example 21.

5-Carbamimidoyl-2-hydroxy-N-[2-(4-isopropyl-2-sulfamoylphenyl)ethyl]-benzenesulfonamide(Compound 52)

¹H-NMR (DMSO-d₆) δ ppm:

1.20 (6H, d, J=6.9 Hz), 2.87-2.97 (3H, m), 3.07 (2H, t, J=7.3 Hz), 6.27(1H, d, J=9.1 Hz), 7.00-7.65 (5H, m), 7.72 (1H, d, J=1.9 Hz), 7.75-7.90(2H, br), 7.95 (1H, d, J=2.8 Hz), 8.40-8.60 (2H, m)

Example 23[2-[2-[(5-Carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]aceticacid (Compound 53)

To a stirred solution of 100 mg ofethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetatein 0.8 mL of ethanol was added 0.183 mL of 2 mol/L sodium hydroxidesolution under ice-cooling. After being stirred at the same temperaturefor 30 minutes, the reaction mixture was concentrated under reducedpressure. To the stirred solution of the residue in a mixture of 0.8 mLof acetonitrile and 0.8 mL of water was added 0.174 mL of 1 mol/Lhydrochloric acid under ice-cooling, and the mixture was stirred at thesame temperature for 5 minutes. To the mixture was added additional0.174 mL of 1 mol/L hydrochloric acid under ice-cooling, and the mixturewas stirred at the same temperature for 5 minutes. The precipitate wascollected by filtration, and washed with water to give 74 mg of[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm:

1.15 (6H, d, J=6.9 Hz), 2.62 (3H, s), 2.73-2.84 (3H, m), 3.40-3.50 (2H,m), 4.33 (2H, s), 4.53 (2H, s), 6.66 (1H, dd, J=7.6, 1.3 Hz), 6.69 (1H,d, J=1.3 Hz), 6.83 (1H, d, J=7.6 Hz), 6.98 (1H, d, J=8.8 Hz), 7.26 (1H,s), 7.72 (1H, dd, J=8.8, 2.5 Hz), 8.12 (1H, d, J=2.5 Hz), 8.48 (2H, brs), 9.14 (2H, br s)

Example 24Amino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]-ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate (Compound 54)

To a stirred solution of 99 mg ofamino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]phenyl]-methylenecarbamoyloxymethyl2,2-dimethylpropionate in 3 mL of tetrahydrofuran was added 9.2 mg of10% palladium on carbon under ice-cooling, and the mixture was stirredunder a hydrogen atmosphere at 30° C. for 1 hour. The insoluble materialwas removed by filtration, and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: ethyl acetate-hexane) to give 75 mg ofamino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]-ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate.

¹H-NMR (CDCl₃) δ ppm:

1.19 (6H, d, J=6.9 Hz), 1.22 (9H, s), 1.35 (3H, t, J=7.3 Hz), 2.73-2.88(3H, m), 3.20-3.32 (2H, m), 4.32 (2H, q, J=7.3 Hz), 4.87 (2H, s), 5.86(2H, s), 6.11 (1H, br s), 6.52 (1H, s), 6.72 (1H, d, J=7.6 Hz), 6.95(1H, d, J=7.6 Hz), 7.01 (1H, d, J=8.8 Hz), 8.08-8.15 (1H, m), 8.20 (1H,d, J=2.2 Hz), 8.72-9.90 (2H, br)

Example 25

The following compounds were prepared according to a similar manner tothat described in Example 24.

Amino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]-ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2-acetoxy-2-methylpropionate (Compound 55)

¹H-NMR (CDCl₃) δ ppm:

1.20 (6H, d, J=6.9 Hz), 1.35 (3H, t, J=7.3 Hz), 1.57 (6H, s), 2.04 (3H,s), 2.75-2.88 (3H, m), 3.22-3.32 (2H, m), 4.32 (2H, q, J=7.3 Hz), 4.69(2H, s), 5.89 (2H, s), 6.12 (1H, br s), 6.51-6.56 (1H, m), 6.73-6.79(1H, m), 6.95 (1H, d, J=7.9 Hz), 7.01 (1H, d, J=8.8 Hz), 8.11 (1H, dd,J=8.8, 2.2 Hz), 8.21 (1H, d, J=2.2 Hz), 8.65-9.95 (2H, m)

Ethyl[4-[2-[5-amino(butoxycarbonylamino)methyl]-2-hydroxybenzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yl]oxyacetate(Compound 56)

¹H-NMR (DMSO-d₆) δ ppm:

0.90 (3H, t, J=7.3 Hz), 1.11 (3H, t, J=7.3 Hz), 1.31-1.40 (2H, m),1.54-1.63 (2H, m), 2.69 (3H, s), 2.74-2.82 (2H, m), 3.02-3.11 (2H, m),4.00 (2H, t, J=6.6 Hz), 4.05 (2H, q, J=7.3 Hz), 4.74 (2H, s), 6.88-6.92(2H, m), 6.96-7.06 (1H, m), 7.15 (1H, d, J=7.6 Hz), 7.19-7.47 (2H, m),7.65 (1H, td, J=7.6, 0.9 Hz), 7.74 (1H, td, J=7.6, 1.3 Hz), 8.00-8.11(2H, m), 8.39 (1H, d, J=1.9 Hz), 8.85-9.35 (2H, m), 11.30-11.70 (1H, br)

EFFECTS OF THE INVENTION

The 5-amidino-2-hydroxybenzenesulfonamide derivatives represented by theabove general formula (I) and pharmaceutically acceptable salts thereofexhibit a potent inhibitory effect on mesangial cell proliferation and adecreasing effect on protein excretion in urine. In addition, thesecompounds exhibit an inhibitory effect on accompanying hypercoagulablestate. Accordingly, pharmaceutical compositions comprising as an activeingredient these compounds can be provided as excellent agents for theprevention or treatment of various renal diseases such as IgAnephropathy, diabetic nephropathy, nephritic syndrome and the like.

1. A method for the treatment of a renal disease selected from the groupconsisting of diabetic nephropathy, IgA nephropathy,membranoproliferative glomerulonephritis, lupus nephritis and purpuranephritis, which comprises administering an effective amount of a5-amidino-2-hydroxybenzenesulfonamide derivative represented by thegeneral formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group which mayhave a substituent selected from the following group (A); (A) —COOR^(A),—CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group, a 6 to 10-memberedaryl group, a 3 to 10-membered heterocycloalkyl group which may have anoxo group, and a 5 to 10-membered aromatic heterocyclic group which mayhave an oxo group or a lower alkyl group; wherein R^(A) represents ahydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkylgroup which may have a substituent selected from the following group(i); (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2) in whichR^(A2) is a 3 to 10-membered cycloalkyl group or a lower alkyl group,—OCOOR^(A3) in which R^(A3) is a 3 to 10-membered cycloalkyl group or alower alkyl group, —OR^(A4) in which R^(A4) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group, —CONR^(A5)R^(A6) inwhich R^(A5) and R^(A6) are independently a hydrogen atom or a loweralkyl group, or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3 to10-membered heterocycloalkyl group and a 5 to 10-membered aromaticheterocyclic group; wherein R^(B) and R^(C) independently represent ahydrogen atom or a lower alkyl group which may have a substituentselected from the following group (ii), or —NR^(B)R^(C) forms a cyclicamino group; (ii) —COOR^(B1) in which R^(B1) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group, —CONR^(B2)R^(C2) inwhich R^(B2) and R^(C2) are independently a hydrogen atom or a loweralkyl group, or —NR^(B2)R^(C2) forms a cyclic amino group, a 3 to10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3 to10-membered heterocycloalkyl group and a 5 to 10-membered aromaticheterocyclic group; T represents an oxygen atom, a sulfur atom or asulfonyl group; or TR¹ represents —SO₂NR^(B3)R^(C3) in which R^(B3) andR^(C3) are independently a hydrogen atom or a lower alkyl group; R²represents a di(lower alkyl)amino group, a lower alkyl group, a 3 to10-membered cycloalkyl group, a 6 to 10-membered aryl group which mayhave one to three substituents selected from the following group (B), a3 to 10-membered heterocycloalkyl group which may have an oxo group, ora 5 to 10-membered aromatic heterocyclic group which may have asubstituent selected from the following group (C); (B) an oxo group, alower alkyl group, a halo(lower alkyl) group, —Y—R^(D), a halogen atom,a nitro group, an amino group, —COOR^(E), a carbamoyl group, a sulfamoylgroup, a lower alkylsulfonyl group, a mono(lower alkyl)sulfamoyl groupwhich may have —COOR^(F), and a lower alkylsulfonylamino-substituted(lower alkyl) group; wherein Y represents an oxygen atom or a sulfuratom; R^(D) represents a hydrogen atom, a halo(lower alkyl) group or alower alkyl group which may have —COOR^(D1) in which R^(D1) is ahydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkylgroup; R^(E) represents a hydrogen atom, a 3 to 10-membered cycloalkylgroup or a lower alkyl group; R^(F) represents a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group; (C) a lower alkylgroup, an amino group and —COOR^(G); wherein R^(G) represents a hydrogenatom, a 3 to 10-membered cycloalkyl group or a lower alkyl group; Qrepresents a hydrogen atom or a lower alkyl group which may have asubstituent selected from the following group (D); (D) —OR^(H),—COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl group which may haveone to three substituents selected from the following group (iii), and a5 to 10-membered aromatic heterocyclic group which may have one to threesubstituents selected from the following group (iv); wherein R^(H)represents a hydrogen atom or a lower alkyl group which may have—OR^(H1) in which R^(H1) is a hydrogen atom or a lower alkyl group;R^(I) independently has the same meaning as R^(A); R^(J) and R^(K)independently represent a hydrogen atom, a 6 to 10-membered aryl groupwhich may have a carbamoyl group, a 5 to 10-membered aromaticheterocyclic group which may have a substituent selected from thefollowing group (v), or a lower alkyl group which may have a substituentselected from the following group (vi), or —NR^(J)R^(K) forms a cyclicamino group which may have a substituent selected from the followinggroup (vii); (v) a halogen atom, a lower alkyl group, a carbamoyl groupand —COOR^(J1) in which R^(J1) is a hydrogen atom or a lower alkylgroup; (vi) —OR^(J2) in which R^(J2) is a hydrogen atom or a lower alkylgroup, and a 5 to 10-membered aromatic heterocyclic group; (vii) ahydroxy group, a lower alkyl group, a hydroxy(lower alkyl) group, acarbamoyl group, a di(lower alkyl)amino group, a lower acyl group and—COOR^(J3) in which R^(J3) is a hydrogen atom or a lower alkyl group;(iii) a halogen atom, a nitro group, a lower alkyl group, —OR^(L) inwhich R^(L) is a hydrogen atom or a lower alkyl group, and —COOR^(M) inwhich R^(M) is a hydrogen atom or a lower alkyl group; (iv) a halogenatom, an oxo group, a lower alkyl group and a phenyl group; and Zrepresents a hydrogen atom, a hydroxy group or —COOR^(N); wherein R^(N)represents a halo(lower alkyl) group, a 6 to 10-membered aryl group, ora lower alkyl group which may have a substituent selected from thefollowing group (viii); (viii) —OR^(N1) in which R^(N1) is a hydrogenatom or a lower alkyl group, —COOR^(N2) in which R^(N2) is a lower alkylgroup which may have —COOR^(N21) where R^(N21) is a lower alkyl group,—CONR^(N3)R^(N4) in which R^(N3) and R^(N4) are independently a hydrogenatom or a lower alkyl group, or —NR^(N3)R^(N4) forms a cyclic aminogroup, —OCOR^(N5) in which R^(N5) is a lower alkyl group which may have—OCOR^(N51) where R^(N51) is a lower alkyl group, a 3 to 10-memberedheterocycloalkyl group and a 6 to 10-membered aryl group, or apharmaceutically acceptable salt thereof.
 2. A method for the treatmentof a renal disease selected from the group consisting of diabeticnephropathy, IgA nephropathy, membranoproliferative glomerulonephritis,lupus nephritis and purpura nephritis, which comprises administering aneffective amount of a 5-amidino-2-hydroxybenzenesulfonamide derivativeclaimed in claim 1 or a pharmaceutically acceptable salt thereof,wherein Q is a hydrogen atom and Z is not a hydrogen atom.
 3. A methodfor the treatment of a renal disease selected from the group consistingof diabetic nephropathy, IgA nephropathy, membranoproliferativeglomerulonephritis, glomerulonephritis, lupus nephritis and purpuranephritis, which comprises administering an effective amount of a5-amidino-2-hydroxy-benzenesulfonamide derivative claimed in claim 1 ora pharmaceutically acceptable salt thereof, wherein R¹ is a lower alkylgroup having —COOR^(A) wherein R^(A) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group which may have asubstituent selected from the following group (i); (i) —COOR^(A1) inwhich R^(A1) is a hydrogen atom, a 3 to 10-membered cycloalkyl group ora lower alkyl group, —OCOR^(A2) in which R^(A2) is a 3 to 10-memberedcycloalkyl group or a lower alkyl group, —OCOOR^(A3) in which R^(A3) isa 3 to 10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) inwhich R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl group ora lower alkyl group, —CONR^(A5)R^(A6) in which R^(A5) and R^(A6) areindependently a hydrogen atom or a lower alkyl group, or —NR^(A5)R^(A6)forms a cyclic amino group, a 3 to 10-membered cycloalkyl group, a 6 to10-membered aryl group, a 3 to 10-membered heterocycloalkyl group and a5 to 10-membered aromatic heterocyclic group; R² is a phenyl grouphaving a substituent selected from the following group (B); (B) an oxogroup, a lower alkyl group, a halo(lower alkyl) group, —Y—R^(D), ahalogen atom, a nitro group, an amino group, —COOR^(E), a carbamoylgroup, a sulfamoyl group, a lower alkylsulfonyl group, a mono(loweralkyl)sulfamoyl group which may have —COOR^(F), and a loweralkylsulfonylamino-substituted (lower alkyl) group; wherein Y is anoxygen atom or a sulfur atom; R^(D) is a hydrogen atom, a halo(loweralkyl) group or a lower alkyl group which may have —COOR^(D1) in whichR^(D1) is a hydrogen atom, a 3 to 10-membered cycloalkyl group or alower alkyl group; R^(E) is a hydrogen atom, a 3 to 10-memberedcycloalkyl group or a lower alkyl group; R^(F) is a hydrogen atom, a 3to 10-membered cycloalkyl group or a lower alkyl group; and T is anoxygen atom; and Z is a hydroxy group.
 4. A method for the treatment ofa renal disease selected from the group consisting of diabeticnephropathy, IgA nephropathy, membranoproliferative glomerulonephritis,lupus nephritis and purpura nephritis, which comprises administering aneffective amount of a 5-amidino-2-hydroxybenzenesulfonamide derivativeclaimed in claim 1 or a pharmaceutically acceptable salt thereof,wherein R¹ is a methyl group having —COOR^(A10) wherein R^(A10) is a 3to 10-membered cycloalkyl group or a lower alkyl group; and R² is aphenyl group having a substituent selected from the group consisting ofa sulfamoyl group, a lower alkylsulfonyl group and a mono(loweralkyl)sulfamoyl group.
 5. A method for the treatment of a renal diseaseselected from the group consisting of diabetic nephropathy, IgAnephropathy, membranoproliferative glomerulonephritis, lupus nephritisand purpura nephritis, which comprises administering an effective amountof a 5-amidino-2-hydroxybenzenesulfonamide derivative claimed in claim 1or a pharmaceutically acceptable salt thereof, wherein R¹ is a loweralkyl group having —COOR^(A10) wherein R^(A10) is a 3 to 10-memberedcycloalkyl group or a lower alkyl group; R² is a phenyl group having asubstituent selected from the group consisting of a sulfamoyl group, alower alkylsulfonyl group and a mono(lower alkyl)sulfamoyl group; Q is ahydrogen atom; T is an oxygen atom; and Z is a hydrogen atom.
 6. Amethod for the treatment of a renal disease selected from the groupconsisting of diabetic nephropathy, IgA nephropathy,membranoproliferative glomerulonephritis, lupus nephritis and purpuranephritis, which comprises administering an effective amount of a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theformula:

or a pharmaceutically acceptable salt thereof.
 7. A method for thetreatment of a renal disease selected from the group consisting ofdiabetic nephropathy, membranoproliferative glomerulonephritis, lupusnephritis and purpura nephritis, which comprises administering aneffective amount of a 5-amidino-2-hydroxybenzenesulfonamide derivativerepresented by the formula:

or a pharmaceutically acceptable salt thereof.
 8. A method for thetreatment of a renal disease selected from the group consisting ofdiabetic nephropathy, IgA nephropathy, membranoproliferativeglomerulonephritis, lupus nephritis and purpura nephritis, whichcomprises administering an effective amount of a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theformula:

or a pharmaceutically acceptable salt thereof.
 9. A method for thetreatment of a renal disease selected from the group consisting ofdiabetic nephropathy, IgA nephropathy, membranoproliferativeglomerulonephritis, lupus nephritis and purpura nephritis, whichcomprises administering an effective amount of a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theformula:

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition for the treatment of a renal disease comprising as an activeingredient (a) a 5-amidino-2-hydroxybenzenesulfonamide derivative asclaimed in claim 1 or a pharmaceutically acceptable salt thereof incombination with one drug selected from the group consisting of (b)antiplatelet drugs, cyclooxygenase inhibitors, immunosuppressant drugs,angiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists, heparin and warfarin.
 11. A method for the treatment of arenal disease, which comprises administering an effective amount of (a)a 5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 1or a pharmaceutically acceptable salt thereof, in combination with onedrug selected from the group consisting of (b) antiplatelet drugs,cyclooxygenase inhibitors, immunosuppressant drugs,angiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists, heparin and warfarin.